Gelatinase inhibitors and prodrugs

ABSTRACT

The invention provides compounds, compositions, and methods for the treatment of diseases, disorders, or conditions that are modulated by matrix metalloproteinases (MMPs). The disease, disorder, or condition can include, for example, stroke, neurological disorders, or ophthalmological disorders. The treatment can include administering a compound or composition described herein, thereby providing a prodrug compound that metabolizes to an active MMP inhibitor in vivo. The MMP inhibition can be selective inhibition, for example, selective inhibition of MMP-2, MMP-9, and/or MMP-14. Thus, the invention provides non-mutagenic prodrug compounds of the formulas described herein that result in the inhibition of MMPs upon in vivo administration.

RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/567,480, filed Dec. 11, 2014, now U.S. Pat. No.9,321,754 issued Apr. 26, 2016; which is a divisional application ofU.S. patent application Ser. No. 13/582,678, filed Nov. 14, 2012, nowU.S. Pat. No. 8,937,151 issued Jan. 20, 2015; which is a National StageApplication of PCT/US2011/027282, filed Mar. 4, 2011; which claimspriority under 35 U.S.C. §119(e) to U.S. Provisional Patent ApplicationNo. 61/310,607, filed Mar. 4, 2010; each of which is incorporated hereinby reference.

BACKGROUND OF THE INVENTION

Evidence is accumulating that damage to neurons and apoptotic death ofneurons play a role in the pathogenesis of many conditions anddisorders, including acute and chronic neurologic disorders. Thesedisorders range from acute stroke, head trauma, and epilepsy to morechronic conditions such as Huntington's disease, Alzheimer's disease,HIV-associated dementia, multiple sclerosis, and glaucoma. Acontributing factor to several of these diseases is the activation ofmatrix metalloproteinases (MMPs) in the extracellular matrix.

MMPs constitute a family of extracellular soluble or membrane-boundproteases that are prominently involved in remodeling the extracellularmatrix. MMP-9 in particular is significantly elevated in humans afterstroke, which is the third leading cause of death in the United States.It is also the primary cause of long-term disability. Acute ischemicstroke, the most common form of stroke, is caused by clotting in thecerebral arteries leading to brain oxygen deprivation and cerebralinfarction. Gelatinases (e.g., MMP-2 and MMP-9) are known to be involvedin neuronal cell death, blood-brain barrier breakdown and hemorrhage.The only FDA-approved drug for the treatment of ischemic stroke istissue plasminogen activator (tPA), a thrombolytic agent. Theadministration of tPA has to be within three hours of the onset ofstroke, resulting in its applicability to less than 5% of strokepatients (CNS Neurol Disord Drug Targets 2008, 7, 243-53). The use oftPA is also limited by serious side effects, which include neurotoxicityand thrombolysis-associated hemorrhagic transformation, and the use oftPA is contraindicated for patients with evidence of hemorrhage or thosewho are taking anti-coagulant medication. Blood from stroke patientsreceiving tPA treatment shows elevated levels of MMP-9, and tPA wasshown to activate MMP-9. Additionally, recent reports indicate that tPAupregulates MMP-9 in the brain and contributes to matrix degradation andbrain damage.

Accordingly, there is a need for new therapies for the treatment ofstroke, and for treatments of stroke that have fewer and/or less severeside effects than currently used therapies. There is also a need for newgelatinase inhibitors, such as selective geleatinase inhibitors, that donot have the side effects of known therapies such as tPa.

SUMMARY

The invention provides a compound of Formula A:

wherein

X is O, —S—NH—, NR^(a) wherein R^(a) is H or (C₁-C₄)alkyl;

R¹ is a solubilizing group comprising 5-30 atoms, in addition tohydrogen, selected from carbon, oxygen, nitrogen, sulfur, andphosphorus, wherein the solubilizing group optionally includes one ormore ester, amide, carboxylic acid, phosphate, carbonate, oxime, imine,carbamate, Mannich base (beta-amino ketone), or ether groups;

each R² is independently H, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, carboxy, cyano,nitro, halo, trifluoromethyl, trifluoromethoxy, SR^(z), SO₂N(R^(z))₂,NR^(z)R^(z), or COOR^(z); wherein each R^(z) is independently H,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₆-C₁₀)aroyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl, heteroaryl(C₁-C₆)alkyl, or optionally a nitrogen protectinggroup when R^(z) is covalently bonded to a nitrogen atom; and

each n is independently 0, 1, 2, 3, or 4;

or a salt thereof;

wherein the compound has an aqueous solubility of at least about 5mg/mL.

In some embodiments, the compound can have an aqueous solubility of atleast about 2.5, at least about 5, at least about 7.5, at least about10, at least about 12.5, at least about 15, at least about 20, at leastabout 25, at least about 30, or at least about 40 mg/mL. In someembodiments, the compound can have an aqueous solubility of at least 2,4, 5, 10, 20, 25, or 30 mM. In yet other embodiments, the compound hasan aqueous solubility of at least about 4000 times, or at least about5000 times that of SB-3CT, which has an aqueous solubility of about 2.45μg/mL.

The compounds of the invention can inhibit matrix metalloproteinases.For example, the compounds can inhibit MMP-2 and have a K_(i) of lessthan about 3 In some embodiments, the compound inhibits MMP-9 and has aK_(i) of less than 20

The variable group R¹—X— can be ortho, meta or para with respect to thephenoxy moiety of Formula A, however, in many embodiments, R¹—X— is metaor para with respect to the phenoxy moiety of Formula A.

In some embodiments, X can be O, NH or —S—NH—, n can be 0, and R¹ canbe:

wherein

L is O, NH, —OCH₂O—, or —C(═O)O—CH₂O—;

each Y is independently —NH₂, —CO₂H, —P(═O)(OH)₂, —OP(═O)(OH)₂, Het, ora guanidine moiety;

Het is a 5 or 6 membered heterocyclic ring comprising 1, 2, or 3heteroatoms selected from O, N, S, or P, wherein the ring optionallyincludes one or two sites of unsaturation and the ring is optionallysubstituted with 1, 2, or 3 oxo, halo, nitro, or methyl groups; and

R³ is an amino acid or a linear or branched chain of two to five aminoacids, linked to X or the carbonyl of R¹ by a nitrogen or sulfur atom;

or a salt thereof.

The invention also provides a compound wherein the compound of Formula Ais a compound of Formula I:

wherein

X is O, NR^(a), or —S—NH—;

R^(a) is H or (C₁-C₄)alkyl;

R¹ is —C(═O)-L-(CH₂)_((m-1))—CH₃, —(C═O)—(CH₂)_(m)—Y;—(C═O)-L-(CH₂)_(m)—Y; —(C═O)—(CHR^(x))—NHR^(y); —P(═O)(OH)₂; an aminoacid; or a linear or branched chain of two to five amino acids;

L is O, NH, —OCH₂O—, or —C(═O)O—CH₂O—;

R^(x) is H or —(CH₂)_(m)Y;

R^(y) is H or —C(═O)—CH(NH₂)—(CH₂)_(m)Y;

m is 1-6;

each Y is independently —NH₂, —CO₂H, —P(═O)(OH)₂, —OP(═O)(OH)₂, Het, ora guanidine moiety;

Het is a 5 or 6 membered heterocyclic ring comprising 1, 2, or 3heteroatoms selected from O, N, S, or P, wherein the ring optionallyincludes one or two sites of unsaturation and the ring is optionallysubstituted with 1, 2, or 3 oxo, halo, nitro, or methyl groups;

each R² is independently H, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, carboxy, cyano,nitro, halo, trifluoromethyl, trifluoromethoxy, SR^(z), SO₂N(R^(z))₂,N^(z)R^(z), or COOR^(z); wherein each R^(z) is independently H,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₆-C₁₀)aroyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl, heteroaryl(C₁-C₆)alkyl, or optionally a nitrogen protectinggroup when covalently bonded to a nitrogen atom; and

each n is independently 0, 1, 2, 3, or 4;

or a salt thereof; and

wherein the compound has an aqueous solubility of at least 5 mM.

In some embodiments, X is O or NH, n is 0, and R¹ is:

wherein

L is O, NH, —OCH₂O—, or —C(═O)O—CH₂O—;

R³ is an amino acid or a linear or branched chain of two to five aminoacids, linked to X by a carbonyl or sulfur residue;

or a salt thereof.

In any embodiment of the invention, each (C₁-C₆)alkyl can beindependently —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or—(CH₂)₆—.

The invention further provides compounds of the following formulas:

wherein X is O or NH;or a salt thereof.

Additionally, a compound of Formula I can be a compound of Formula II orFormula III:

wherein

X is O or NH;

R³ is an amino acid moiety selected from Ala, Cys, Asp, Glu, Phe, Gly,His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, Tyr, ortaurine, optionally protected on any nitrogen, sulfur, or carboxylicacid with a protecting group, or a non-natural amino acid, for example,selected from phosphoserine; phosphothreonine; phosphotyrosine;hydroxyproline; γ-carboxyglutamate; hippuric acid;octahydroindole-2-carboxylic acid; statine;1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid; penicillamine;ornithine; citrulline; α-methyl-alanine; para-benzoyl-phenylalanine;phenylglycine; propargylglycine; sarcosine; and tert-butylglycine; or

R³ is a combination of any two to five amino acids in a linear orbranched configuration; and

R⁴ is a residue of a sulfur-containing amino acid linked to Formula IIIby its sulfur atom shown as part of Formula III;

or a salt thereof. When the sulfur-containing amino acid linked toFormula III is taurine, the sulfur of Formula III can be the sulfonylgroup of taurine (i.e., the sulfur bonded to R⁴ can be a sulfonyl).

The invention additionally provides a pharmaceutical compositioncomprising a compound of a formula as described herein and apharmaceutically acceptable diluent or carrier. The pharmaceuticalcomposition can be formulated for intravenous, subcutaneous,intracardiac, intramuscular, intraperatoneal, or topical administration.

Accordingly, the invention provides a method of treating a disease orcondition that is modulated by a matrix metalloproteinase (MMP)comprising administering to a patient in need of such treatment aneffective amount of a compound of a formula described herein, so thatthe disease or condition is treated. The matrix metalloproteinase (MMP)can be a gelatinase (e.g., MMP-2, MMP-9, or MMP-13), a collagenase, astromelysin, MMP-23, MMP-19, or matrilysin, and the activity of thematrix metalloproteinase can be significantly inhibited.

When the compounds, compositions, or methods of the invention are usedto inhibit MMPs, the inhibition may be selective for one type of MMPover one or more others. In some embodiments, a compound can selectivelyinhibit MMP-2, MMP-9, and/or MMP-14. The manner of inhibition may alsoinvolve slow-binding inhibition with respect to k_(on) and k_(off)parameters, as documented in Table 2 of Example 2. Accordingly,modulating a matrix metalloproteinase or inhibiting a matrixmetalloproteinase includes selectively inhibiting a matrixmetalloproteinase, such as MMP-2, MMP-9, and/or MMP-14, while othergelatinases, such as MMP-1, MMP-3, and/or MMP-7 are not inhibited.

The disease or condition can include any disease, disorder, or conditionrecited herein, including, but not limited to, cancer, stroke, a chronicwound, an ophthalmological disorder, traumatic brain injury, spinal cordinjury, subarachnoid hemorrhage, tuberculosis, asthma, glaucoma, retinalischemia, ischemic optic neuropathy, macular degeneration, sequalae ofhyperhomocystinemia, convulsion, pain, aneurism, depression, anxiety,schizophrenia, muscle spasm, migraine headache, urinary incontinence,drug withdrawal, nicotine withdrawal, opiate tolerance or withdrawal,emesis, brain edema, tardive dyskinesia, AIDS-induced dementia, oculardamage, retinopathy, a cognitive disorder, or a neuronal injuryassociated with HIV-infection; or a gelatinase-mediatedneurodegenerative disorder comprising epilepsy, Alzheimer's disease,Huntington's disease, Parkinson's disease, multiple sclerosis, oramyotrophic lateral sclerosis; or a combination thereof.

In some embodiments, the condition is ischemic stroke or hemorrhagicstroke. In another embodiment, the condition is a neurological disorderor ophthalmological disorder. The neurological disorder orophthalmological disorder can arise from at least one of trauma,ischemic or hypoxic conditions. The neurological disorder can be aneurodegenerative disorder. In some embodiments, the disease, disorder,or condition may arise from at least one of painful neuropathy,neuropathic pain, diabetic neuropathy, drug dependence, drug withdrawal,drug addiction, depression, anxiety, movement disorders, tardivedyskinesia, cerebral infections that disrupt the blood-brain barrier,meningitis, meningoencephalitis, hypoglycemia, cerebral ischemia(stroke), cardiac arrest, spinal cord trauma, head trauma, perinatalhypoxia, or hypoglycemic neuronal damage.

The administering of a compound described herein can be carried out incombination with administering a thrombolytic agent. The thrombolyticagent can be, for example, tissue plasminogen activator (tPA).

The invention provides for the use of a compound described herein toprepare a medicament to treat a disease or condition that is modulatedby a matrix metalloproteinase (MMP). The medicament can include aphysiologically acceptable diluent or carrier.

The invention thus provides novel compounds of Formula A and Formula I,intermediates for their synthesis, as well as methods of preparing suchcompounds. The invention also provides compounds of the formulasdescribed herein that are useful as intermediates for the synthesis ofother useful compounds. The invention further provides for the use ofcompounds of Formula A and Formula I for the manufacture of medicamentsuseful for the treatment of various conditions modulated by matrixmetalloproteinases, such as stroke in a mammal.

Additionally, the invention provides compounds and compositionsdescribed herein for use in medical therapy. The medical therapy can betreating a neurological disorder or cancer, such as breast cancer, lungcancer, pancreatic cancer, prostate cancer, or colon cancer. Additionaldiseases, disorders, and conditions that can be treated with suchtherapy are described herein below. The invention also provides for theuse of a compound or composition described herein for the manufacture ofa medicament to treat such conditions, for example, conditions in amammal, such as a human. The medicament can include a pharmaceuticallyacceptable diluent, excipient, or carrier. The invention furtherprovides for the use of a compound or composition described herein toprepare a medicament for treating such disorders in a mammal, such as ahuman.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference. Reference is herein made to the subjectmatter recited by certain claims, examples of which are illustrated inthe accompanying structures and formulas. While the exemplary subjectmatter will be described, it will be understood that the exemplarydescriptions are not intended to limit the claims. On the contrary, theinventive subject matter is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the presently disclosed subject matter as defined by the claims.

Introduction

The discovery and synthesis of SB-3CT, the first prototypemechanism-based inhibitor for MMPs (K_(i) 14±1 nM and 600±200 nM forhuman MMP-2 and MMP-9, respectively) was reported in 2000 (J. Amer.Chem. Soc. 2000, 122, 6799-6800; J. Biol. Chem. 2000, 275, 41415-23).The K_(i) values for other MMPs tested in the μM range at best.

The selectivity of SB-3CT for inhibition of gelatinases over all otherMMPs is due to the ability of gelatinase to facilitate the requisiterate-limiting deprotonation event leading to thiirane-ring opening,giving tight-binding inhibition by the thiolate generated within theactive site. SB-3CT was evaluated in a mouse transient ischemia modeland found to reduce infarct volume to 30% of control and significantlyimproved neurobehavioral scores. Notably, administration of SB-3CT at 6hours after ischemia potently blocked histological damage. Furthermore,SB-3CT has been shown to be effective for the treatment of viral-inducedvascular leakage in mice, a model of hemorrhagic fever, and in a ratmodel of subarachnoid hemorrhage, a type of hemorrhagic stroke. Thus, aselective gelatinase inhibitor can be used for treatment of bothischemic and hemorrhagic stroke.

These studies indicate that MMP-9 and MMP-2 contribute in the diseaseprocess of stroke. Gelatinase inhibitors can protect the neurovascularintegrity of the brain from ischemia or exogenous tPA thrombolysis byblocking degradation of the basal membrane laminin and exertinganti-apoptotic effects on neurons. Therefore, combined treatment withselective gelatinase inhibitors and tPA can minimize neurotoxicity andhemorrhagic transformation associated with tPA use, thereby extendingthe window of treatment for reperfusion therapy of tPA.

For this approach to effectively treat stroke patients, it requiresdelivery of the gelatinase inhibitors by intravenous administration. Theprototype selective gelatinase inhibitor SB-3CT has poor aqueoussolubility (2.45 μg/mL), therefore it cannot be administeredintravenously. In addition, SB-3CT is rapidly metabolized by oxidationat the para position of the terminal phenyl ring and at the α-positionwith respect to the sulfonyl group. The p-hydroxylated metabolite was amore potent gelatinase inhibitor than the parent SB-3CT (K_(i) 6±3 nMand 160±80 nM for human MMP-2 and MMP-9, respectively). More than 400second-generation gelatinase inhibitors have been synthesized that aremore water soluble, more metabolically stable, and more potentinhibitors than the parent SB-3CT. These second-generation gelatinaseinhibitors contain functional groups that can be used in a prodrugstrategy to improve the aqueous solubility and pharmacokineticproperties of the gelatinase inhibitors.

A prodrug (drug+pro-moiety or solubilizing group) is a chemical entitywith little or no pharmacological activity that undergoes transformationto the therapeutically active drug in the body. Water-soluble prodrugsof second-generation gelatinase inhibitors have been prepared asdescribed herein. These inhibitors rapidly generate the active drug inthe bloodstream. The prodrugs are designed to release naturallyoccurring non-toxic pro-moieties during the transformation to thetherapeutically active drug. The prodrug gelatinase inhibitors are atleast 5000-fold more water soluble than SB-3CT and are amenable tointravenous administration. This novel therapeutic strategy by itself orin combination with tPA would reduce injury and extend the time windowfor thrombolytic therapy in patients with stroke.

DEFINITIONS

As used herein, the recited terms have the following meanings. All otherterms and phrases used in this specification have their ordinarymeanings as one of skill in the art would understand. Such ordinarymeanings may be obtained by reference to technical dictionaries, such asHawley's Condensed Chemical Dictionary 14^(th) Edition, by R. J. Lewis,John Wiley & Sons, New York, N.Y., 2001.

References in the specification to “one embodiment”, “an embodiment”,etc., indicate that the embodiment described may include a particularaspect, feature, structure, moiety, or characteristic, but not everyembodiment necessarily includes that aspect, feature, structure, moiety,or characteristic. Moreover, such phrases may, but do not necessarily,refer to the same embodiment referred to in other portions of thespecification. Further, when a particular aspect, feature, structure,moiety, or characteristic is described in connection with an embodiment,it is within the knowledge of one skilled in the art to affect orconnect such aspect, feature, structure, moiety, or characteristic withother embodiments, whether or not explicitly described.

The singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, a referenceto “a compound” includes a plurality of such compounds, so that acompound X includes a plurality of compounds X. It is further noted thatthe claims may be drafted to exclude any optional element. As such, thisstatement is intended to serve as antecedent basis for the use ofexclusive terminology, such as “solely,” “only,” and the like, inconnection with the recitation of claim elements or use of a “negative”limitation.

The term “and/or” means any one of the items, any combination of theitems, or all of the items with which this term is associated. Thephrase “one or more” is readily understood by one of skill in the art,particularly when read in context of its usage. For example, one or moresubstituents on a phenyl ring refers to one to five, or one to four, forexample if the phenyl ring is disubstituted.

The term “about” can refer to a variation of ±5%, ±10%, ±20%, or ±25% ofthe value specified. For example, “about 50” percent can in someembodiments carry a variation from 45 to 55 percent. For integer ranges,the term “about” can include one or two integers greater than and/orless than a recited integer. Unless indicated otherwise herein, the term“about” is intended to include values, e.g., weight percents, proximateto the recited range that are equivalent in terms of the functionalityof the individual ingredient, the composition, or the embodiment.

As will be understood by the skilled artisan, all numbers, includingthose expressing quantities of ingredients, properties such as molecularweight, reaction conditions, and so forth, are approximations and areunderstood as being optionally modified in all instances by the term“about.” These values can vary depending upon the desired propertiessought to be obtained by those skilled in the art utilizing theteachings of the descriptions herein. It is also understood that suchvalues inherently contain variability necessarily resulting from thestandard deviations found in their respective testing measurements.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges recited herein also encompass any and all possible sub-ranges andcombinations of sub-ranges thereof, as well as the individual valuesmaking up the range, particularly integer values. A recited range (e.g.,weight percents or carbon groups) includes each specific value, integer,decimal, or identity within the range. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths, ortenths. As a non-limiting example, each range discussed herein can bereadily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art, all languagesuch as “up to,” “at least,” “greater than,” “less than,” “more than,”“or more,” and the like, include the number recited and such terms referto ranges that can be subsequently broken down into sub-ranges asdiscussed above. In the same manner, all ratios recited herein alsoinclude all sub-ratios falling within the broader ratio. Accordingly,specific values recited for radicals, substituents, and ranges, are forillustration only; they do not exclude other defined values or othervalues within defined ranges for radicals and substituents.

One skilled in the art will also readily recognize that where membersare grouped together in a common manner, such as in a Markush group, theinvention encompasses not only the entire group listed as a whole, buteach member of the group individually and all possible subgroups of themain group. Additionally, for all purposes, the invention encompassesnot only the main group, but also the main group absent one or more ofthe group members. The invention therefore envisages the explicitexclusion of any one or more of members of a recited group. Accordingly,provisos may apply to any of the disclosed categories or embodimentswhereby any one or more of the recited elements, species, orembodiments, may be excluded from such categories or embodiments, forexample, as used in an explicit negative limitation.

The term “contacting” refers to the act of touching, making contact, orof bringing to immediate or close proximity, including at the cellularor molecular level, for example, to bring about a physiologicalreaction, a chemical reaction, or a physical change, e.g., in asolution, in a reaction mixture, in vitro, or in vivo.

The terms “comprising”, “including”, “having”, and “composed of” areopen-ended terms as used herein.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to about 20 carbon atoms in the chain. For example, thealkyl group can be a (C₁-C₂₀)alkyl, a (C₁-C₁₂)alkyl, (C₁-C₈)alkyl,(C₁-C₆)alkyl, or (C₁-C₄)alkyl. Examples of alkyl groups include methyl(Me, which also may be structurally depicted by a/symbol), ethyl (Et),n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (t-Bu),pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that inlight of the ordinary skill in the art and the teachings provided hereinwould be considered equivalent to any one of the foregoing examples.Alkyl groups can be optionally substituted or unsubstituted, andoptionally partially unsaturated, such as in an alkenyl group.

The term “alkenyl” refers to a straight- or branched-chain alkenyl grouphaving from 2 to 20 carbon atoms in the chain. (The double bond of thealkenyl group is formed by two sp² hybridized carbon atoms.)Illustrative alkenyl groups include C₁-C₁₂ alkenyl groups, such asprop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl,and groups that in light of the ordinary skill in the art and theteachings provided herein would be considered equivalent to any one ofthe foregoing examples. Alkenyl groups can be optionally substituted orunsubstituted.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle, and can be optionally substituted orunsubstituted. In some embodiments, an alkyl group refers to acycloalkyl group that accordingly includes a ring structure. Such alkylgroups include (cycloalkyl)-alkyl groups. Illustrative examples ofcycloalkyl groups include the following entities, in the form ofproperly bonded moieties:

A “heterocycle” or “heterocycloalkyl” group refers to a monocyclic, orfused, bridged, or spiro polycyclic ring structure that is saturated orpartially saturated and has from 3 to 12 ring atoms per ring structureselected from carbon atoms and up to three heteroatoms selected fromnitrogen, oxygen, and sulfur. The ring structure may optionally containup to two oxo groups on carbon or sulfur ring members, and can beoptionally substituted or unsubstituted. Illustrative examples ofheterocycle groups include the following entities, in the form ofproperly bonded moieties:

The term “aryl” refers to an aromatic hydrocarbon group derived from theremoval of at least one hydrogen atom from a single carbon atom of aparent aromatic ring system. The radical attachment site can be at asaturated or unsaturated carbon atom of the parent ring system. The arylgroup can have from 6 to 30 carbon atoms, for example, about 6-14 carbonatoms, about 6-13 carbon atoms, or about 6-10 carbon atoms. The arylgroup can have a single ring (e.g., phenyl) or multiple condensed(fused) rings, wherein at least one ring is aromatic (e.g., naphthyl,dihydrophenanthrenyl, fluorenyl, or anthryl). Typical aryl groupsinclude, but are not limited to, radicals derived from benzene,naphthalene, anthracene, biphenyl, and the like. The aryl can beunsubstituted or optionally substituted.

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. The heteroaryl can be unsubstituted or optionallysubstituted. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkyl,heterocycle, and heteroaryl groups listed or illustrated above are notexhaustive, and that additional species within the scope of thesedefined terms may also be selected.

As used herein, the term “Het” can refer to a 5 or 6 memberedheterocyclic ring comprising 1, 2, or 3 heteroatoms selected from O, N,S, or P, wherein the ring optionally includes one or two cites ofunsaturation and the ring is optionally substituted with 1, 2, or 3 oxo,halo, nitro, or methyl groups. The Het group can be a heterocycle groupor a heteroaryl group. Examples include oxadiazoles, thiadiazoles,oxazoles, thiazoles, diazines, triazoles, and tetrazoles. In oneembodiment, Het specifically refers to 1,3,4-oxadiazoles,1,2,4-oxadiazoles, the isomeric 1,2,4-oxadiazoles, tetrazoles,1,3,4-thiadiazoles, oxazoles, 1,2-diazines, thiazoles, and1,3,4-triazoles. In another specific embodiment, Het specifically refersto 1,2-diazine, a thiazole, a 1,2,4-oxadiazole, a 1,3,4-thiadiazole, a1,3,4-triazole, or a tetrazole. In yet another embodiment, Hetspecifically refers to a 1,2,4-oxadiazole, or a 1,3,4-thiadiazole. Inother embodiments, Het can refer to a 5-membered heterocyclic ringwherein the ring includes three heteroatoms independently selected fromO, S, P, and N. In some embodiments, at least two of the heteroatoms areN. In some embodiments, at least two of the heteroatoms are 0. In yetother embodiments, Het is specifically any 1, 2, 3, 4, 5, 6, 7, or 8groups selected from 1,3,4-oxadiazoles, 1,2,4-oxadiazoles, the isomeric1,2,4-oxadiazoles, tetrazoles, 1,3,4-thiadiazoles, oxazoles,1,2-diazines, thiazoles, and 1,3,4-triazoles.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

As to any of the groups or “substituents” described herein, each canfurther include one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents. Itis understood, of course, that such groups do not contain anysubstitution or substitution patterns which are sterically impracticaland/or synthetically non-feasible.

The term “substituted” means that a specified group or moiety can bearone or more (e.g., 1, 2, 3, 4, 5, or 6) substituents. The term“unsubstituted” means that the specified group bears no substituents.The term “optionally substituted” means that the specified group isunsubstituted or substituted by one or more substituents. Where the term“substituted” is used to describe a structural system, the substitutionis meant to occur at any valency-allowed position on the system. Incases where a specified moiety or group is not expressly noted as beingoptionally substituted or substituted with any specified substituent, itis understood that such a moiety or group is intended to beunsubstituted in some embodiments but can be substituted in otherembodiments. Suitable substituent groups include, e.g., alkyl, alkenyl,alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, aroyl,heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino,alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl,acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy,carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkyl sulfonyl,arylsulfinyl, aryl sulfonyl, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclesulfinyl, heterocyclesulfonyl, phosphate, sulfate, hydroxylamine, hydroxyl (alkyl)amine, and/or cyano. In certain embodiments, anyone of the above groups can be included or excluded from a variable orfrom a group of substituents.

Specific values listed below for substituents (i.e., groups) and rangesare for illustration only. They do not exclude other defined values orother values within defined ranges for the substituents.

Specifically, (C₁-C₆)alkyl can be, for example, methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;

(C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy,iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;

(C₂-C₆)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl;

(C₂-C₆)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl;

(C₁-C₆)alkanoyl can be acetyl, propanoyl or butanoyl;

(C₂-C₆)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy,isobutanoyloxy, pentanoyloxy, or hexanoyloxy;

(C₃-C₈)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, or cyclooctyl;

aryl can be phenyl, indenyl, 5,6,7,8-tetrahydronaphthyl, or naphthyl.;and

bicyclic aryl can be indenyl or naphthyl.

Het can be heteroaryl, monocyclic heteroaryl, bicyclic heteroaryl, or anon-aromatic heterocycle. Heteroaryl can be furyl, imidazolyl,tetrazolyl, pyridyl (or its N-oxide), thienyl, pyrimidinyl (or itsN-oxide), indolyl, or quinolyl (or its N-oxide); monocyclic heteroarylcan be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl,thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl,pyridyl (or its N-oxide), thienyl, or pyrimidinyl (or its N-oxide);andbicyclic heteroaryl can be quinolyl (or its N-oxide); and bicyclicalkyl can be decahydroquinoline or decahydronaphthalene (cis or trans).The Het group can optionally include, for example, one or two cites ofunsaturation, and the ring can optionally be substituted with 1, 2, 3,or 4 substituents, for example, oxo, halo, nitro, or methyl groups.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric and/or diastereomeric forms. All optical isomers andstereoisomers of the compounds of the general formula, and mixturesthereof, are considered within the scope of the formula. Thus, anyformula given herein is intended to represent a racemate, one or moreenantiomeric forms, one or more diastereomeric forms, one or moreatropisomeric forms, and/or mixtures thereof. Furthermore, certainstructures may exist as geometric isomers (i.e., cis and trans isomers),as tautomers, or as atropisomers. Additionally, any formula given hereinis intended to embrace hydrates, solvates, and polymorphs of suchcompounds, and mixtures thereof.

The invention also specifically includes the racemic, scalemic, R, and Smixtures and forms at the thiirane moiety of compounds of Formula A,Formula I, and their associated formulas. Accordingly, in someembodiments, the stereochemistry of the thiirane chiral center is in theR configuration, and in some embodiments, the stereochemistry of thethiirane chiral center is in the S configuration. Compounds of bothconfigurations actively inhibit MMPs.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²⁵I, respectively.

Such isotopically labeled compounds are useful in metabolic studies(preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or³H), detection or imaging techniques [such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)]including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to limit the definition of the moiety for thevariable appearing elsewhere. In other words, where a variable appearsmore than once, the choice of the species from a specified list isindependent of the choice of the species for the same variable elsewherein the formula, or elsewhere in a different formula.

The term “amino acid” includes but is not limited to the following 20naturally-occurring proteogenic amino acid residues:

SYMBOL: DEFINITION SYMBOL: DEFINITION Ala Alanine Met Methionine CysCysteine Asn Asparagine Asp Aspartic Acid Pro Proline Glu Glutamic AcidGln Glutamine Phe Phenylalanine Arg Arginine Gly Glycine Ser Serine HisHistidine Thr Threonine Ile Isoleucine Val Valine Lys Lysine TrpTryptophan Leu Leucine Tyr Tyrosine

Thus, an “amino acid” can be a natural amino acid residue (e.g., Ala,Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met,Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, taurine, or anunnatural amino acid (e.g., phosphoserine; phosphothreonine;phosphotyrosine; hydroxyproline; gamma-carboxyglutamate; hippuric acid;octahydroindole-2-carboxylic acid; statine;1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; penicillamine;ornithine; citrulline; α-methyl-alanine; para-benzoylphenylalanine;phenylglycine; propargylglycine; sarcosine; and tert-butylglycine)residue having one or more open valences. The term also comprisesnatural and unnatural amino acids bearing amino protecting groups (e.g.acetyl, acyl, trifluoroacetyl, or benzyloxycarbonyl), as well as naturaland unnatural amino acids protected at carboxy with protecting groups(e.g., as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide). Othersuitable amino and carboxy protecting groups are known to those skilledin the art (See for example, T. W. Greene, Protecting Groups In OrganicSynthesis; Wiley: New York, 1981; D. Voet, Biochemistry, Wiley: NewYork, 1990; L. Stryer, Biochemistry, (3rd Ed.), W.H. Freeman and Co.:New York, 1975; J. March, Advanced Organic Chemistry, Reactions,Mechanisms and Structure, (2nd Ed.), McGraw Hill: New York, 1977; F.Carey and R. Sundberg, Advanced Organic Chemistry, Part B: Reactions andSynthesis, (2nd Ed.), Plenum: New York, 1977; and references citedtherein). According to the invention, the amino or carboxy protectinggroup can also comprise a radionuclide (e.g., Fluorine-18, Iodine-123,or Iodine-124).

Modified and protected amino acid residues, as well as peptido-mimetics,are also intended to be encompassed within the definition of “aminoacid” or a linear or branched chain of two to five amino acids. As wouldbe readily recognized by one skilled in the art, the amino acid can belinked to the remainder of the compound through its carbonyl residue,its amino residue, or through a sulfur residue if the amino acidincludes a thiol group. A linear or branched chain of two to five aminoacids can include any combination of two to five Ala, Cys, Asp, Glu,Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val,Trp, or Tyr, optionally protected on nitrogen, sulphur, or a carboxylicacid with protecting groups.

A combination of two to five amino acids can be referred to as a“peptide”. A peptide can also be a sequence of 2 to about 10 amino acids(e.g., as defined hereinabove) or peptidic residues having an openvalences to link to a formula described herein. The sequence may belinear or cyclic. For example, a cyclic peptide can be prepared or mayresult from the formation of disulfide bridges between two cysteineresidues in a sequence. A peptide can be linked through the carboxyterminus, the amino terminus, or through any other convenient point ofattachment, such as, for example, through the sulfur of a cysteine.Peptide derivatives can be prepared as described in U.S. Pat. No.4,612,302 (Szabo et al.); U.S. Pat. No. 4,853,371 (Coy et al.); and U.S.Pat. No. 4,684,620 (Hruby et al.).

Prodrugs and Metabolites

The invention also relates to pharmaceutically acceptable prodrugs ofSB-3CT, and treatment methods using such prodrugs. The term “prodrug”refers to a precursor of a designated compound that, followingadministration to a subject, yields the compound in vivo via a chemicalor physiological process such as solvolysis, enzymatic cleavage, orenzymatic biotransformation, or under physiological conditions (e.g.,where a prodrug upon being brought to physiological pH is converted tothe compound hydroxy-SB-3CT). A “pharmaceutically acceptable prodrug” isa prodrug that is non-toxic, biologically tolerable, and otherwisebiologically suitable for administration to the subject. Illustrativeprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Design of Prodrugs, H.Bundgaard, Ed.; Elsevier, 1985.

Examples of prodrugs include compounds of formula A wherein thesolubilizing group is an amino acid residue, or a polypeptide chain oftwo or more (e.g., two, three or four) amino acid residues, covalentlyjoined through an amide or ester bond to a free amino or hydroxy, suchas the hydroxy group of hydroxy-SB-3CT. Examples of amino acid residuesinclude the twenty naturally occurring amino acids, commonly designatedby three letter symbols, as well as 4-hydroxyproline, hydroxylysine,demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine,methionine sulfone, taurine, and protected versions thereof.

Additional types of a prodrug may be produced, for instance, byderivatizing (chemically converting) the hydroxyl group to an amide oralkyl ester or an amino group to an amide or secondary amine (e.g.,thereby providing a ‘solubilizing group’). Examples of amides includethose derived from ammonia, primary C₁₋₆alkyl amines and secondarydi(C₁₋₆alkyl) amines. Secondary amines include 5- or 6-memberedheterocycloalkyl or heteroaryl ring moieties. Examples of amides includethose that are derived from ammonia, C₁₋₃alkyl primary amines, anddi(C₁₋₂alkyl)amines. Examples of esters of the invention includeC₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆alkyl) esters.Preferred esters include methyl esters. Prodrugs may also be prepared byderivatizing free hydroxy groups using groups including hemisuccinates,phosphate esters, dimethylaminoacetates, andphosphoryloxy-methyloxycarbonyls, following procedures such as thoseoutlined in Adv. Drug Delivery Rev. 1996, 19, 115. Carbamate derivativesof hydroxy and amino groups may also yield prodrugs. Suitabletransformations well know to those of skill in the art are described byGreg T. Hermanson in Bioconjugate Techniques, Academic Press, San Diego,Calif. (1996). Other useful transformations are described in U.S. PatentPublication No. 2009/0005420 (Lee et al.).

Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxygroups may also provide prodrugs. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may bean alkyl ester, optionally substituted with one or more ether, amine, orcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, is also useful to yield prodrugs.Prodrugs of this type may be prepared as described in J. Med. Chem.1996, 39, 10. Free amines can also be derivatized as amides,sulfonamides or phosphonamides. These prodrug moieties may incorporategroups including ether, amine, and carboxylic acid functionalities.

The present invention also relates to a method of providing apharmaceutically active metabolite of a compound of a formula describedherein, and uses of such a metabolite in the methods of the invention. A“pharmaceutically active metabolite” refers to a pharmacologicallyactive product of metabolism in the body of a compound of a formuladescribed herein. A prodrug or an active metabolite of a compound may bedetermined using routine techniques known or available in the art. See,e.g., Bertolini, et al., J. Med. Chem. 1997, 40, 2011-2016; Shan, etal., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res.1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 224-331; Bundgaard,Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design andApplication of Prodrugs, Drug Design and Development (Krogsgaard-Larsen,et al., eds., Harwood Academic Publishers, 1991).

Compounds and Methods of the Invention

A compound of a formula described herein, or a pharmaceuticallyacceptable salt thereof, can be administered to a mammal (e.g., human)alone or in conjunction with a second agent, such as a neurologicalagent, or a pharmaceutically acceptable salt thereof. Accordingly, thecompound can be administered in conjunction with a thrombolytic agent,such as tPA to treat a disorder, disease, or condition as describedherein.

The term “neurological agent” refers to a compound, including chemicaland biological compounds (e.g., peptides, oligonucleotides andantibodies), that has an effect on the nervous system, e.g., compoundscapable of treating, inhibiting or preventing disorders affecting thenervous system or compounds capable of eliciting a neurological and/oran ophthalmological disorder or symptoms thereof.

Specific examples of the compounds of Formula A and Formula I include:

the preparation of which are described in the examples section below.Other compounds of Formula A and Formula I that can be readily preparedusing the techniques described herein as well as those well known tothose of skill in the art include:

where R is an amino acid or a peptide, such as a linear or branchedchain of two to five amino acids. For techniques well known in the art,see for example, March, Advanced Organic Chemistry, Reactions,Mechanisms and Structure, 2^(nd) Ed., 1977 and Carey & Sundberg,Advanced Organic Chemistry, Part B: Reactions, 2^(nd) Ed., 1983.

Protecting Groups

Compounds of the invention include compounds of Formula A and Formula I,as well as such compounds that also include suitable protecting groups.The term “protecting group” refers to any group that, when bound to ahydroxyl, nitrogen, or other heteroatom prevents undesired reactionsfrom occurring at this group and that can be removed by conventionalchemical or enzymatic steps to reestablish the ‘unprotected’ hydroxyl,nitrogen, or other heteroatom group. The particular removable groupemployed is often interchangeable with other groups in various syntheticroutes. Certain removable protecting groups include conventionalsubstituents such as, for example, allyl, benzyl, acetyl, chloroacetyl,thiobenzyl, benzylidene, phenacyl, methyl methoxy, silyl ethers (e.g.,trimethylsilyl (TMS), t-butyl-diphenylsilyl (TBDPS), triisopropylsilyl(TIPS), or t-butyldimethylsilyl (TBS)) and any other group that can beintroduced chemically onto a hydroxyl functionality and laterselectively removed either by chemical or enzymatic methods in mildconditions compatible with the nature of the product.

A large number of protecting groups and corresponding chemical cleavagereactions are described in Protective Groups in Organic Synthesis,Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN0-471-62301-6) (“Greene”, which is incorporated herein by reference inits entirety). Greene describes many nitrogen protecting groups, forexample, amide-forming groups. In particular, see Chapter 1, ProtectingGroups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups,pages 21-94, Chapter 4, Carboxyl Protecting Groups, pages 118-154, andChapter 5, Carbonyl Protecting Groups, pages 155-184. See alsoKocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart,New York, 1994), which is incorporated herein by reference in itsentirety. Some specific protecting groups that can be employed inconjunction with the methods of the invention are discussed below.

Typical nitrogen and oxygen protecting groups described in Greene (pages14-118) include benzyl ethers, silyl ethers, esters including sulfonicacid esters, carbonates, sulfates, and sulfonates. For example, suitablenitrogen or oxygen protecting groups can include substituted methylethers; substituted ethyl ethers; p-chlorophenyl, p-methoxyphenyl,2,4-dinitrophenyl, benzyl; substituted benzyl ethers (p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,diphenylmethyl, 5-dibenzosuberyl, triphenylmethyl,p-methoxyphenyl-diphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 1,3-benzodithiolan-2-yl, benzisothiazolylS,S-dioxido); silyl ethers (silyloxy groups) (trimethylsilyl,triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl, t-butylmethoxy-phenylsilyl); esters (formate,benzoylformate, acetate, choroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate)); carbonates (methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenyl sulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl,allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate,4-ethoxy-1-naphthyl, methyl dithiocarbonate); groups with assistedcleavage (2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate,o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate,2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate,miscellaneous esters (2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3 tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate (tigolate),o-(methoxycarbonyl)benzoate, p-poly-benzoate, a-naphthoate, nitrate,alkyl N,N,N′,N′-tetramethyl-phosphorodiamidate, n-phenylcarbamate,borate, 2,4-dinitrophenylsulfenate); and sulfonates (sulfate,methanesulfonate (mesylate), benzylsulfonate, tosylate, triflate).

Pharmaceutical Salts and Solvates

The invention also includes pharmaceutically acceptable salts and/orsolvates of the compounds represented by a formula described herein,such as those described above and of the specific compounds exemplifiedherein, and methods of treatment using such salts and/or solvates.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by a formula describedherein that is non-toxic, biologically tolerable, or otherwisebiologically suitable for administration to the subject. See, generally,S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977,66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection,and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.Preferred pharmaceutically acceptable salts are those that arepharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response.

Pharmaceutically acceptable salts include the addition salts ofinorganic acids such as hydrochloride, hydrobromide, hydroiodide,halide, sulfate, phosphate, carbonate, bicarbonate, diphosphate andnitrate or of organic acids such as acetate, malonate, maleate,fumarate, tartrate, succinate, citrate, lactate, benzoate, ascorbate,tosylate, mesylate, trifluoromethanesulphonate, palmoate, stearate,α-ketoglutarate, and α-glycerophosphate. Also within the scope of thepresent invention, when they can be used, are the salts formed frombases such as sodium or potassium hydroxide. For other examples ofpharmaceutically acceptable salts, reference can be made to “Saltselection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.

A compound of a formula described herein may possess a sufficientlyacidic group, a sufficiently basic group, or both types of functionalgroups, and accordingly react with a number of inorganic or organicbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt. Examples of pharmaceutically acceptable salts includesulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, behenates,besylates, propionates, decanoates, caprylates, acrylates, formates,isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates,succinates, suberates, sebacates, fumarates, maleates,butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates,phthalates, sulfonates, xylenesulfonates, phenylacetates,phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates,propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,and mandelates.

If the compound of a formula described herein contains a basic nitrogen,the desired pharmaceutically acceptable salt may be prepared by anysuitable method available in the art, for example, treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoricacid, and the like, or with an organic acid, such as acetic acid,phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbicacid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid,valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as mandelic acid, citric acid, or tartaricacid, an amino acid, such as aspartic acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

If the compound of a formula described herein includes an acid moiety,such as a carboxylic acid or sulfonic acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide,alkaline earth metal hydroxide, any compatible mixture of bases such asthose given as examples herein, and any other base and mixture thereofthat are regarded as equivalents or acceptable substitutes in light ofthe ordinary level of skill in this technology. Illustrative examples ofsuitable salts include organic salts derived from amino acids, such asglycine and arginine, ammonia, carbonates, bicarbonates, primary,secondary, and tertiary amines, and cyclic amines, such as benzylamines,pyrrolidines, piperidine, morpholine, and piperazine, and inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum, and lithium.

The term “solvate” refers to a solid compound that has one or moresolvent molecules associated with its solid structure. Solvates can formwhen a compound is crystallized from a solvent, wherein one or moresolvent molecules become integral part(s) of the crystal. The compoundsof a formula described herein can be solvates, for example, ethanolsolvates. Likewise, a “hydrate” refers to a solid compound that has oneor more water molecules associated with its solid structure. A hydrateis a subgroup of solvates. Hydrates can form when a compound iscrystallized from water, wherein one or more water molecules becomeintegral part(s) of the crystal. The compounds of a formula describedherein can be hydrates.

Therapeutic Methods

A compound of Formula A or Formula I or a pharmaceutically acceptablesalt or solvate thereof, and its pharmaceutically active metabolite(collectively, “active agents”) are useful as MMP inhibitors, or forproviding MMP inhibitors in vivo, in the methods of the invention.Accordingly, the prodrug compounds described herein can be inactive asMMP inhibitors but can become active agents (inhibitors) in vivo afteradministration to a patient in need of such treatment. The active agentsmay be used for the treatment or prevention of medical conditions,diseases, or disorders mediated through inhibition or modulation ofvarious MMPs, such as those described herein. Active agents according tothe invention may therefore be used as analgesics, anti-depressants,cognition enhancers, neuroprotectants, sedatives, appetite stimulants,or contraceptives, as well as useful treatments for the conditionsdescribed below.

Described herein are numerous diseases and conditions that might appearto be unrelated but each is related by shared mechanistic attributes.Each disease or condition described herein is gelatinase-dependent. Forexample, both auto-controlled growth and the ability to metastasize areassociated with cancer. The prodrug compounds described herein canprovide compounds in vivo that are anti-proliferative and areanti-metastatic toward matrix metalloproteinase dependent diseases.

Compounds and pharmaceutical compositions suitable for use in theinvention include those wherein the active agent is administered in aneffective amount to achieve its intended purpose. The phrase“therapeutically effective amount” refers to an amount effective totreat the disease, disorder, and/or condition, for example, an amounteffective to reduce the progression or severity of the condition orsymptoms being treated. Determination of a therapeutically effectiveamount is well within the capacity of persons skilled in the art. Theterm “effective amount” can include an amount of a compound describedherein, or an amount of a combination of compounds described herein,e.g., to treat or prevent a disease or disorder, or to treat thesymptoms of the disease or disorder, in a host. Thus, an “effectiveamount” generally means an amount that provides the desired effect.

The terms “treating”, “treat” and “treatment” can include (i) preventinga disease, pathologic or medical condition from occurring (e.g.,prophylaxis); (ii) inhibiting the disease, pathologic or medicalcondition or arresting its development; (iii) relieving the disease,pathologic or medical condition; and/or (iv) diminishing symptomsassociated with the disease, pathologic or medical condition. Thus, theterms “treat”, “treatment”, and “treating” extend to prophylaxis andinclude prevent, prevention, preventing, lowering, stopping or reversingthe progression or severity of the condition or symptoms being treated.As such, the term “treatment” can include each of medical, therapeutic,and/or prophylactic administration, as appropriate.

The terms “inhibit”, “inhibiting”, and “inhibition” refer to theslowing, halting, or reversing the growth or progression of a disease,infection, condition, or group of cells. The inhibition can be greaterthan about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, comparedto the growth or progression that occurs in the absence of the treatmentor contacting.

Exemplary medical conditions, diseases, and disorders include anxiety,depression, pain, sleep disorders, eating disorders, inflammation,multiple sclerosis and other movement disorders, HIV wasting syndrome,closed head injury, stroke, learning and memory disorders, Alzheimer'sdisease, epilepsy, Tourette's syndrome, epilepsy, Niemann-Pick disease,Parkinson's disease, Huntington's chorea, optic neuritis, autoimmuneuveitis, symptoms of drug withdrawal, nausea, emesis, sexualdysfunction, post-traumatic stress disorder, or cerebral vasospasm, orcombinations thereof, as well as the conditions described below.

The active agents may be used to treat subjects (patients) diagnosedwith or suffering from a disease, disorder, or condition that ismediated through MMP activity, e.g., one of the 26 known gelatinases.The term “treat” or “treating” as used herein is intended to refer toadministration of an agent or composition of the invention to a subjectfor the purpose of effecting a therapeutic or prophylactic benefitthrough modulation of MMP activity. Treating includes reversing,ameliorating, alleviating, inhibiting the progress of, lessening theseverity of, or preventing a disease, disorder, or condition, or one ormore symptoms of such disease, disorder or condition mediated throughmodulation of MMP activity.

The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human. “Modulators” include both inhibitors andactivators, where “inhibitors” refer to compounds that decrease,prevent, inactivate, desensitize or down-regulate MMP expression oractivity, and “activators” are compounds that increase, activate,facilitate, sensitize, or up-regulate MMP expression or activity.

Accordingly, the invention relates to methods of using the active agentsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated through MMP activity, such asanxiety, pain, sleep disorders, eating disorders, inflammation, ormovement disorders (e.g., multiple sclerosis).

Symptoms or disease states are intended to be included within the scopeof “medical conditions, disorders, or diseases.” For example, pain maybe associated with various diseases, disorders, or conditions, and mayinclude various etiologies. Illustrative types of pain treatable with aMMP-modulating agent according to the invention include cancer pain,postoperative pain, GI tract pain, spinal cord injury pain, visceralhyperalgesia, thalamic pain, headache (including stress headache andmigraine), low back pain, neck pain, musculoskeletal pain, peripheralneuropathic pain, central neuropathic pain, neurodegenerative disorderrelated pain, and menstrual pain. HIV wasting syndrome includesassociated symptoms such as appetite loss and nausea. Parkinson'sdisease includes, for example, levodopa-induced dyskinesia.

Treatment of multiple sclerosis may include treatment of symptoms suchas spasticity, neurogenic pain, central pain, or bladder dysfunction.Symptoms of drug withdrawal may be caused by, for example, addiction toopiates or nicotine. Nausea or emesis may be due to chemotherapy,postoperative, or opioid related causes. Treatment of sexual dysfunctionmay include improving libido or delaying ejaculation. Treatment ofcancer may include treatment of glioma. Sleep disorders include, forexample, sleep apnea, insomnia, and disorders calling for treatment withan agent having a sedative or narcotic-type effect. Eating disordersinclude, for example, anorexia or appetite loss associated with adisease such as cancer or HIV infection/AIDS.

The invention also provides a composition comprising a compound of anyone of the formulas described herein and a pharmaceutically acceptablediluent or carrier. The pharmaceutical composition can include athrombolytic agent or an analgesic, such as an opioid or a non-steroidalanti-inflammatory drug. Examples of such analgesics include aspirin,acetaminophen, opioids, ibuprofen, naproxen, COX-2 inhibitors,gabapentin, pregabalin, tramadol, or combinations thereof.

The term “thrombolytic agent” refers to a drug that is able to dissolvea clot or “thrombus” and reopen an artery or vein. Thrombolytic agentsmay be used to treat a heart attack, stroke, deep vein thrombosis (e.g.,a clot in a deep leg vein), pulmonary embolism, and occlusion of aperipheral artery or indwelling catheter. Thrombolytic agents are serineproteases and they convert plasminogen to plasmin, which breaks downfibrinogen and fibrin and dissolves blood clots. Currently availablethrombolyic agents include reteplase (r-PA or Retavase), alteplase (t-PAor Activase), urokinase (Abbokinase), prourokinase, anisoylated purifiedstreptokinase activator complex (APSAC), and streptokinase. Thrombolyticagents are also called clotbusters, clot-dissolving medications, andfibrinolyic agents.

Accordingly, the invention also provides a method of treating a subjectsuffering from or diagnosed with a disease, disorder, or medicalcondition mediated by MMP activity, comprising administering to thesubject in need of such treatment an effective amount of at least onecompound of a formula described herein, a pharmaceutically acceptablesalt thereof, a pharmaceutically acceptable prodrug thereof, or apharmaceutically active metabolite thereof. The disease, disorder, ormedical condition can include anxiety, depression, pain, sleepdisorders, eating disorders, inflammation, movement disorders, HIVwasting syndrome, closed head injury, stroke, learning and memorydisorders, Alzheimer's disease, epilepsy, Tourette's syndrome,Niemann-Pick disease, Parkinson's disease, Huntington's chorea, opticneuritis, autoimmune uveitis, drug withdrawal, nausea, emesis, sexualdysfunction, post-traumatic stress disorder, cerebral vasospasm,glaucoma, irritable bowel syndrome, inflammatory bowel disease,immunosuppression, gastroesophageal reflux disease, paralytic ileus,secretory diarrhea, gastric ulcer, rheumatoid arthritis, unwantedpregnancy, hypertension, cancer, hepatitis, allergic airway disease,autoimmune diabetes, intractable pruritus, neuroinflammation, or acombination thereof.

The invention further includes a pharmaceutical composition for treatinga disease, disorder, or medical condition mediated by MMP activity,comprising: (a) an effective amount of at least one compound of aformula described herein, or a pharmaceutically acceptable salt, apharmaceutically acceptable prodrug, or a pharmaceutically activemetabolite thereof, or any combination thereof, and a pharmaceuticallyacceptable excipient. The invention also includes a method of inhibitingfatty acid amide hydrolase activity comprising contacting the fatty acidamide hydrolase with an effective amount of a compound of any one of theformulas described herein. The contacting can be in vivo or in vitro.

The compounds described herein are generally non-mutagenic. Thenon-mutagenic nature of a compound can be with or without metabolicactivation. Mutagenic potential can be evaluated, for example, bymeasuring a compound's ability to induce reverse mutations at selectedloci of Ames II mixed strains and/or strain TA98 in the presence andabsence of rat liver S9 metabolic activation (e.g., at concentrations upto 1 mg/mL (equivalent to 300 μM)).

Pharmaceutical Formulations

The compounds described herein can be used to prepare therapeuticpharmaceutical compositions. The compounds may be added to thecompositions in the form of a salt or solvate. For example, in caseswhere compounds are sufficiently basic or acidic to form stable nontoxicacid or base salts, administration of the compounds as salts may beappropriate. Examples of pharmaceutically acceptable salts includeorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, as described in the section onPharmaceutical Salts and Solvates. Suitable inorganic salts may also beformed, as described in the section on Pharmaceutical Salts andSolvates.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid to provide aphysiologically acceptable ionic compound. Alkali metal (for example,sodium, potassium or lithium) or alkaline earth metal (for example,calcium) salts of carboxylic acids can also be prepared by analogousmethods.

The compounds of the formulas described herein can be formulated aspharmaceutical compositions and administered to a mammalian host, suchas a human patient, in a variety of forms. The forms can be specificallyadapted to a chosen route of administration, e.g., oral or parenteraladministration, or by intravenous, intramuscular, intracardiac,intraperatoneal, topical or subcutaneous routes.

The compounds described herein may be systemically administered incombination with a pharmaceutically acceptable vehicle, such as an inertdiluent or an assimilable edible carrier. For oral administration,compounds can be enclosed in hard or soft shell gelatin capsules,compressed into tablets, or incorporated directly into the food of apatient's diet. Compounds may also be combined with one or moreexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.Such compositions and preparations typically contain at least 0.1% ofactive compound. The percentage of the compositions and preparations canvary and may conveniently be from about 2% to about 60% of the weight ofa given unit dosage form. The amount of active compound in suchtherapeutically useful compositions is such that an effective dosagelevel can be obtained.

The tablets, troches, pills, capsules, and the like may also contain oneor more of the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; and a lubricant such as magnesium stearate. A sweeteningagent such as sucrose, fructose, lactose or aspartame; or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring, maybe added. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propyl parabens as preservatives, a dye andflavoring such as cherry or orange flavor. Any material used inpreparing any unit dosage form should be pharmaceutically acceptable andsubstantially non-toxic in the amounts employed. In addition, the activecompound may be incorporated into sustained-release preparations anddevices.

The active compound may be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water or saline, optionallymixed with a nontoxic surfactant. Dispersions can be prepared inglycerol, liquid polyethylene glycols, triacetin, or mixtures thereof,or in a pharmaceutically acceptable oil. Under ordinary conditions ofstorage and use, preparations may contain a preservative to prevent thegrowth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions, dispersions, or sterile powderscomprising the active ingredient adapted for the extemporaneouspreparation of sterile injectable or infusible solutions or dispersions,optionally encapsulated in liposomes. The ultimate dosage form should besterile, fluid and stable under the conditions of manufacture andstorage. The liquid carrier or vehicle can be a solvent or liquiddispersion medium comprising, for example, water, ethanol, a polyol (forexample, glycerol, propylene glycol, liquid polyethylene glycols, andthe like), vegetable oils, nontoxic glyceryl esters, and suitablemixtures thereof. The proper fluidity can be maintained, for example, bythe formation of liposomes, by the maintenance of the required particlesize in the case of dispersions, or by the use of surfactants. Theprevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thiomersal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, buffers, or sodium chloride. Prolonged absorption of theinjectable compositions can be brought about by agents delayingabsorption, for example, aluminum monostearate and/or gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousother ingredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation can include vacuumdrying and freeze drying techniques, which yield a powder of the activeingredient plus any additional desired ingredient present in thepreviously sterile-filtered solutions.

For topical administration, compounds may be applied in pure form, e.g.,when they are liquids. However, it will generally be desirable toadminister the active agent to the skin as a composition or formulation,for example, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Useful liquidcarriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, orwater-alcohol/glycol blends, in which a compound can be dissolved ordispersed at effective levels, optionally with the aid of non-toxicsurfactants. Adjuvants such as fragrances and additional antimicrobialagents can be added to optimize the properties for a given use. Theresultant liquid compositions can be applied from absorbent pads, usedto impregnate bandages and other dressings, or sprayed onto the affectedarea using a pump-type or aerosol sprayer.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses, or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of dermatological compositions for delivering active agents tothe skin are known to the art; for example, see Jacquet et al. (U.S.Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S.Pat. No. 4,559,157), and Wortzman (U.S. Pat. No. 4,820,508). Suchdermatological compositions can be used in combinations with thecompounds described herein.

Useful dosages of the compounds described herein can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949 (Borch et al.). The amount of a compound, or anactive salt or derivative thereof, required for use in treatment willvary not only with the particular compound or salt selected but alsowith the route of administration, the nature of the condition beingtreated, and the age and condition of the patient, and will beultimately at the discretion of an attendant physician or clinician.

The compound can be conveniently administered in a unit dosage form, forexample, containing 5 to 1000 mg/m², conveniently 10 to 750 mg/m², mostconveniently, 50 to 500 mg/m² of active ingredient per unit dosage form.The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

In one embodiment, the invention provides therapeutic methods oftreating cancer in a mammal, which involve administering to a mammalhaving cancer an effective amount of a compound or composition describedherein. A mammal includes a primate, human, rodent, canine, feline,bovine, ovine, equine, swine, caprine, bovine and the like. Cancerrefers to any various type of malignant neoplasm, for example, breastcancer, colon cancer, lung cancer, prostate cancer, melanoma andleukemia, and in general is characterized by an undesirable cellularproliferation, e.g., unregulated growth, lack of differentiation, localtissue invasion, and metastasis.

The ability of a compound of the invention to treat cancer may bedetermined by using assays well known to the art. For example, thedesign of treatment protocols, toxicity evaluation, data analysis,quantification of tumor cell kill, and the biological significance ofthe use of transplantable tumor screens are known.

Combination Therapy

In the following description, component “(b)” is to be understood torepresent one or more agents as described herein (e.g., a compound ofFormula A or Formula I). Thus, if components (a) and (b) are to betreated the same or independently, each agent of component (b) may alsobe treated the same or independently. Components (a) and (b) may beformulated together, in a single dosage unit (that is, combinedtogether, e.g., in one lotion, cream, gel, ointment, or formulation forinjection) as a combination product. When component (a) and (b) are notformulated together in a single dosage unit, the component (a) may beadministered at the same time as component (b), or in any order. Forexample component (a) may be administered first, followed byadministration of component (b), or they may be administered in thereverse order. If component (b) contains more than one agent, e.g., athrombolytic agent and NSAID, these agents may be administered togetheror separately in any order. When not administered at the same time, theadministration of component (a) and (b) occurs less than about ten hoursapart, or about one hour apart in some embodiments.

As is appreciated by a medical practitioner skilled in the art, thedosage of the combination therapy of the invention may vary dependingupon various factors such as the pharmacodynamic characteristics of theparticular agent and its mode of administration, the age, health andweight of the recipient, the nature and extent of the symptoms, the kindof concurrent treatment, the frequency of treatment, and the effectdesired, as described above. The proper dosage of components (a) and (b)will be readily ascertainable by a medical practitioner skilled in theart. By way of general guidance, typically a daily dosage may be about100 milligrams to about 1.5 grams of each component. If component (b)represents more than one compound, then typically a daily dosage may beabout 100 milligrams to about 1.5 grams of each agent of component (b).By way of general guidance, when the compounds of component (a) andcomponent (b) are administered in combination, the dosage amount of eachcomponent may be reduced by about 50-80% relative to the usual dosage ofthe component when it is administered alone as a single agent for thetreatment of a disorder, and related symptoms, in view of synergisticeffect of the combination.

Pharmaceutical kits useful for the treatment of disorders describedherein, and related symptoms, which include a therapeutically effectiveamount of a pharmaceutical composition that includes a compound ofcomponent (a) and one or more compounds of component (b), in one or moresterile containers, are also within the ambit of the invention.Sterilization of the container may be carried out using conventionalsterilization methodology well known to those skilled in the art.Component (a) and component (b) may be in the same sterile container orin separate sterile containers. The sterile containers of materials mayinclude separate containers, or one or more multi-part containers, asdesired. Component (a) and component (b), may be separate, or physicallycombined into a single dosage form or unit as described above. Such kitsmay further include, if desired, one or more of various conventionalpharmaceutical kit components, such as for example, one or morepharmaceutically acceptable carriers, additional vials for mixing thecomponents, etc., as will be readily apparent to those skilled in theart. Instructions, either as inserts or as labels, indicating quantitiesof the components to be administered, guidelines for administration,and/or guidelines for mixing the components, may also be included in thekit.

The MMP inhibitor can optionally be co-administered with aneuroprotectant drug, used, for example, in the treatment of Alzheimer'sdisease or other neurologic or ophthalmologic disorders (e.g.,glaucoma), including, but not limited to, memantine or a derivativethereof.

The MMP inhibitor can optionally be co-administered with at least one ofthe following:

An anti glaucoma agent, beta adrenergic blocking agent, carbonicanhydrase inhibitor, miotic agent, sympathomimetic agent, acetylcholineblocking agent, antihistamine, anti-viral agent, quinolone,anti-inflammatory agent, non-steroidal anti-inflammatory agent,steroidal anti-inflammatory agent, antidepressant (e.g., serotoninreuptake inhibitors, SSRIs), psychotherapeutic agent, anti-anxietyagent, analgesic, antiseizure agent, anti-convulsant, gabapentine,anti-hypertensive agent, benzoporphyrin phtosensitiser,immunosuppressive antimetabolite, anti-convulsant, barbiturate,benzodiazipine, GABA inhibitors, hydantoin, antipsychotic, neurolaptic,antidysknetic, adrenergic agent, tricyclic antidepressant,anti-hypoglycemic, glucose solution, plypeptide hormone, antibiotic,thrombolytic agent, blood thinner, antiarrhythmic agent, corticosteroid,seizure disorder agent, anticholinesterase, dopamine blocker,antiparkinsonian agent, muscle relaxant, anxiolytic muscle relaxant, CNSstimulant, antiemetic, beta adrenergic blocking agents, ergotderivative, isometheptene, antiserotonin agent, analgesic, selectiveserotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitor, aidsadjunct agents, anti infective agent, systemic aids adjunct antiinfective, aids chemotherapeutic agent, nucleoside reversetranscriptase, a protease inhibitor, or a thrombolytic agent such astPA.

Specifically, the MMP inhibitor can optionally be co-administered withat least one of the following:

A beta adrenergic blocking agent, carbonic anhydrase inhibitor,cholinesterase inhibitor, cholinergic (miotic), docosanoid,prostaglandin, tricyclic antidepressant, psychotherapeutic agent,antianxiety agent, analgesic, anti-seizure agent, tricyclicantidepressants having analgesic effect in neuropathic pain, linolenicacid, coenzyme, vitamin, immunosuppressive antimetabolite, antiviral,copolymer, barbiturate, benzodiazepine, GABA inhibitor, hydantoin,tranquilizer, antipsychotic, norephedrine, peptide, antibacterial,tissue plasminogen activator (TPA), blood thinner/anticoagulant,cardiostimulant, carbonic anhydrase inhibitor, ketoderivative ofcarbamazepine, acetylcholinesterase, antipsychotic, alkaloid, GABA-Breceptor agonist, benzodiazepine, antiparkinsonian, antidepressant, CNSstimulant, receptor antagonist, beta adrenergic blocking agent, ergotderivatives (anti migraine), anticonvulsant, serotonin (5-HT) receptoragonist, antimanic, SSRI, MAOI, aids adjunct anti infective agent,antiviral, and protease inhibitor.

Additionally, the MMP inhibitor can optionally be co-administered withat least one of the following:

Timolol Maleate; Betaxolol HCl; Carteolol HCl; Metipranolol; TimololHemihydrate; Brimonidine Tartarate; Brinzolamide; Dorzolamide;Acetazolamide; Echothiophate Iodide; Pilocarpine HCl; UnoprostoneIsopropyl ester; Latanoprost; Acamprosate, a drug with additionalneuroprotective properties; Amitriptyline; Perphenazine;Chlordiazepoxide; Trimipramine Maleate; Chlodiazepoxide HCl; Alprazolam;Hydroxyzine dihydrochloride; Meprobamate; Doxipin HCl; HydroxyzinePamoate; Aspirin; Acetaminophen; Ibuprofen; Carbamazipine; Flupirtine, adrug with neuroprotective properties using additional pathways to MMPantagonists; Lamotrigine; Phenytoin Sodium; Pentaxifylline; ThiocticAcid; Levocarnitine; Biotin; Nicotinic acid; Taurine; Verteporfin;Azathioprine; Interferon Beta 1β, a glycoprotein containing 166 aminoacids; Interferon Beta 1α, a glycoprotein containing 166 amino acids;Cyclophosphamide; Methotrexate; Neurmexane, an NMDAR antagonist withimproved properties compared to memantine; Glatiramer, an L-GlutamicAcid Polymer with L-alanine, L-lycine, and L-tyrocine; Mephobarbitol;Pentobarbitol; Lorazipam; Clonazepam; Chlorazeptate Dipotassium salt;Fosphenytoin Sodium; Olanzapine; Heloperidol; Trifluoperizine;Fluphenazine; Phenylpropanol amine; Pseudoephedrine HCl; Imipramine;Glucagon; Glucagon-related peptide-1, a 37 amino acid peptide;Glucagon-related peptide-2, a peptide that contains 33 amino acids;Penicilin G,N,O, or V; Ampicillin; Chloramphenicol; Phorbol; Heparin,D-glucosamine with L-iduronic or D-glucuronic acids; Warfarin;Epinephrine; Amiodarone; Lidocaine; Nitroglycerin, isosorbide dinitrate,amyl, butyl, isobutyl or various other nitrates that have been shown tobe neuroprotective; Atenolol; Dexamethasone; Prednisolone;Acetazolamide; Phenytoin; Tiagabin HCl; Gabapentin; Oxacarbazepine;Tacrine; Donepezil; Rivastigmine; Heloperidol; Phenothiazine; Reserpine;Tetrabenazene; Bromocryptine; Tiapride; Baclofen; Diazepam;Trihexyphenidyl HCl; Amitrityline; Amphetamines; Methylphenidate;Amitriptylinec; Clomipramine; Dolasetron; Granisetron; Huperzine, anherb used for dementia; Metoclopramide; Prochlorperazine; Dexamethasone;Timolol Hydrogen maleate salt; Propanolol; Isometheptine; Atenolol;Metoprolol; Nadolol; Ergotamine; Dihydroargotamine; Naratriptan;Sumatriptan; Rizatriptan; Zolmitriptan; Imipramine HCl; Dopamine;Clozapine; Valproic Acid; Amitriptylinec; Imipramine HCl; ImipraminePamoate; Clomipramine; Amphetamine; Methylphenidate; Phenytoin;Phenobarbital; Amitryptyline; Imipramine Pamoate; Nortrityline;Trazodone; Nefazodone; Sertraline; Fluoxetine; Paroxetine; Phenalzine;Tranylcypromine; Erythropoietin, a glycoprotein; Immunoglobulins (gammaglobulins); Tetrahydrocannabinols; Alitretinoin; Lamivudin; Stavudin;Zalcitabine; Abacavir; Ritonavir; Indinavir; and Nelfinavir; thechemical names of which are well known in the art and are also describedin U.S. Publication No. 2009/0209615 (Liption et al.), which isincorporated herein by reference. Any one or more of the above compoundscan be used in a pharmaceutically acceptable salt form, solvate form(e.g., a mono- or di-hydrate), or any combination thereof

Diseases, Disorders, and Conditions

The term “neurological disorder” refers to any disorder of the nervoussystem and/or visual system. “Neurological disorders” include disordersthat involve the central nervous system (brain, brainstem andcerebellum), the peripheral nervous system (including cranial nerves),and the autonomic nervous system (parts of which are located in bothcentral and peripheral nervous system). Neurodegenerative disorder alsorefers to a type of neurological disease marked by the loss of nervecells, including, but not limited to, Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, tauopathies (includingfronto-temporal dementia), and Huntington's disease.

Major groups of neurological disorders include, but are not limited to,headache, stupor and coma, dementia, seizure, sleep disorders, trauma,infections, neoplasms, neuroophthalmology, movement disorders,demyelinating diseases, spinal cord disorders, and disorders ofperipheral nerves, muscle and neuromuscular junctions. Addiction andmental illness, include, but are not limited to, bipolar disorder andschizophrenia, are also included in the definition of neurologicaldisorder. The following is a list of several neurological disorders,symptoms, signs and syndromes: Acquired Epileptiform Aphasia; AcuteDisseminated Encephalomyelitis; Adrenoleukodystrophy; Agenesis of thecorpus callosum; Agnosia; Aicardi syndrome; Alexander disease; Alpers'disease; Alternating hemiplegia; Alzheimer's disease; Amyotrophiclateral sclerosis; Anencephaly; Angelman syndrome; Angiomatosis; Anoxia;Aphasia; Apraxia; Arachnoid Cysts; Arachnoiditis; Arnold-Chiarimalformation; Arteriovenous malformation; Asperger syndrome; AtaxiaTelangiectasia; Attention Deficit Hyperactivity Disorder; Autism;Autonomic Dysfunction; Back Pain; Batten disease; Behcet's disease;Bell's palsy; Benign Essential Blepharospasm; Benign Focal; Amyotrophy;Benign Intracranial Hypertension; Binswanger's disease; Blepharospasm;Bloch Sulzberger syndrome; Brachial plexus injury; Brain abscess; Braininjury; Brain tumors (including Glioblastoma multiforme); Spinal tumor;Brown-Sequard syndrome; Canavan disease; Carpal tunnel syndrome (CTS);Causalgia; Central pain syndrome; Central pontine myelinolysis; Cephalicdisorder; Cerebral aneurysm; Cerebral arteriosclerosis; Cerebralatrophy; Cerebral gigantism; Cerebral palsy; Charcot-Marie-Toothdisease; Chemotherapy-induced neuropathy and neuropathic pain; Chiarimalformation; Chorea; Chronic inflammatory demyelinating polyneuropathy(CIDP); Chronic pain; Chronic regional pain syndrome; Coffin Lowrysyndrome; Coma, including Persistent Vegetative State; Congenital facialdiplegia; Corticobasal degeneration; Cranial arteritis;Craniosynostosis; Creutzfeldt-Jakob disease; Cumulative traumadisorders; Cushing's syndrome; Cytomegalic inclusion body disease(CIBD); Cytomegalovirus Infection; Dancing eyes-dancing feet syndrome;Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome;Dejerine-Klumpke palsy; Dementia; Dermatomyositis; Diabetic neuropathy;Diffuse sclerosis; Dysautonomia; Dysgraphia; Dyslexia; Dystonias; Earlyinfantile epileptic encephalopathy; Empty sella syndrome; Encephalitis;Encephaloceles; Encephalotrigeminal angiomatosis; Epilepsy; Erb's palsy;Essential tremor; Fabry's disease; Fahr's syndrome; Fainting; Familialspastic paralysis; Febrile seizures; Fisher syndrome; Friedreich'sataxia; Fronto-Temporal Dementia and other “Tauopathies”; Gaucher'sdisease; Gerstmann's syndrome; Giant cell arteritis; Giant cellinclusion disease; Globoid cell Leukodystrophy; Guillain-Barre syndrome;HTLV-1 associated myelopathy; Hallervorden-Spatz disease; Head injury;Headache; Hemifacial Spasm; Hereditary Spastic Paraplegia; Heredopathiaatactica polyneuritiformis; Herpes zoster oticus; Herpes zoster;Hirayama syndrome; HIV-Associated Dementia and Neuropathy (see alsoNeurological manifestations of AIDS); Holoprosencephaly; Huntington'sdisease and other polyglutamine repeat diseases; Hydranencephaly;Hydrocephalus; Hypercortisolism; Hypoxia; Immune-Mediatedencephalomyelitis; Inclusion body myositis; Incontinentia pigmenti;Infantile; phytanic acid storage disease; Infantile Refsum disease;Infantile spasms; Inflammatory myopathy; Intracranial cyst; Intracranialhypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease;Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease;Kugelberg-Welander disease; Kuru; Lafora disease; Lambert-Eatonmyasthenic syndrome; Landau-Kleffner syndrome; Lateral medullary(Wallenberg) syndrome; Learning disabilities; Leigh's disease;Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; Leukodystrophy; Lewy bodydementia; Lissencephaly; Locked-In syndrome; Lou Gehrig's disease (akaMotor Neuron Disease or Amyotrophic Lateral Sclerosis); Lumbar discdisease; Lyme disease-Neurological Sequelae; Machado-Joseph disease;Macrencephaly; Megalencephaly; Melkersson-Rosenthal syndrome; Menieresdisease; Meningitis; Menkes disease; Metachromatic leukodystrophy;Microcephaly; Migraine; Miller Fisher syndrome; Mini-Strokes;Mitochondrial Myopathies; Mobius syndrome; Monomelic amyotrophy; MotorNeurone Disease; Moyamoya disease; Mucopolysaccharidoses; Multi-InfarctDementia; Multifocal motor neuropathy; Multiple sclerosis and otherdemyelinating disorders; Multiple system atrophy with posturalhypotension; Muscular dystrophy; Myasthenia gravis; Myelinoclasticdiffuse sclerosis; Myoclonic encephalopathy of infants; Myoclonus;Myopathy; Myotonia congenital; Narcolepsy; Neurofibromatosis;Neuroleptic malignant syndrome; Neurological manifestations of AIDS;Neurological sequelae of lupus; Neuromyotonia; Neuronal ceroidlipofuscinosis; Neuronal migration disorders; Niemann-Pick disease;O'Sullivan-McLeod syndrome; Occipital Neuralgia; Occult SpinalDysraphism Sequence; Ohtahara syndrome; Olivopontocerebellar Atrophy;Opsoclonus Myoclonus; Optic neuritis; Orthostatic Hypotension; Overusesyndrome; Paresthesia; Parkinson's disease; Paramyotonia Congenita;Paraneoplastic diseases; Paroxysmal attacks; Parry Romberg syndrome;Pelizaeus-Merzbacher disease; Periodic Paralyses; Peripheral Neuropathy;Painful Neuropathy and Neuropathic Pain; Persistent Vegetative State;Pervasive developmental disorders; Photic sneeze reflex; Phytanic AcidStorage disease; Pick's disease; Pinched Nerve; Pituitary Tumors;Polymyositis; Porencephaly; Post-Polio syndrome; Postherpetic Neuralgia(PHN); Postinfectious Encephalomyelitis; Postural Hypotension;Prader-Willi syndrome; Primary Lateral Sclerosis; Prion diseases;Progressive; Hemifacial Atrophy; Progressive multifocalleukoencephalopathy; Progressive Sclerosing Poliodystrophy; ProgressiveSupranuclear Palsy; Pseudotumor cerebri; Ramsay-Hunt syndrome (Type Iand Type II); Rasmussen's Encephalitis; Reflex Sympathetic Dystrophysyndrome; Refsum disease; Repetitive Motion Disorders; Repetitive StressInjuries; Restless Legs syndrome; Retrovirus-Associated Myelopathy; Rettsyndrome; Reye's syndrome; Saint Vitus Dance; Sandhoff disease;Schilder's disease; Schizencephaly; Septo-Optic Dysplasia; Shaken Babysyndrome; Shingles; Shy-Drager syndrome; Sjogren's syndrome; SleepApnea; Soto's syndrome; Spasticity; Spina bifida; Spinal cord injury;Spinal cord tumors; Spinal Muscular Atrophy; Stiff-Person syndrome;Stroke; Sturge-Weber syndrome; Subacute Sclerosing Panencephalitis;Subarachnoid Hemorrhage; Subcortical Arteriosclerotic Encephalopathy;Sydenham Chorea; Syncope; Syringomyelia; Tardive dyskinesia; Tay-Sachsdisease; Temporal arteritis; Tethered Spinal Cord syndrome; Thomsendisease; Thoracic Outlet syndrome; Tic Douloureux; Todd's Paralysis;Tourette syndrome; Transient ischemic attack; Transmissible SpongiformEncephalopathies; Transverse myelitis; Traumatic Brain injury; Tremor;Trigeminal Neuralgia; Tropical Spastic Paraparesis; Tuberous Sclerosis;Vascular Dementia (Multi-Infarct Dementia); Vasculitis includingTemporal Arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg'ssyndrome; Werdnig-Hoffman disease; West syndrome; Whiplash; Williamssyndrome; Wilson's disease; and Zellweger syndrome.

The term “ophthalmologic disease” or “ophthalmologic disorder” refers toa disease or disorder involving the anatomy and/or function of thevisual system, including but not limited to, glaucoma, retinal arteryocclusion, ischemic optic neuropathy and wet or dry maculardegeneration.

A neurological disorder can be an affective disorder (e.g., depressionor anxiety). The term “affective disorder” or “mood disorder” refers toa variety of conditions characterized by a disturbance in mood as themain feature. If mild and occasional, the feelings may be normal. Ifmore severe, they may be a sign of a major depressive disorder ordysthymic reaction or be symptomatic of bipolar disorder. Other mooddisorders may be caused by a general medical condition. See, Mosby'sMedical, Nursing & Allied Health Dictionary, 5th Edition (1998).

The term “depression” refers to an abnormal mood disturbancecharacterized by feelings of sadness, despair, and discouragement.Depression refers to an abnormal emotional state characterized byexaggerated feelings of sadness, melancholy, dejection, worthlessness,emptiness, and hopelessness, that are inappropriate and out ofproportion to reality. See, Mosby's Medical, Nursing & Allied HealthDictionary, 5th Edition (1998). Depression can be at least one of amajor depressive disorder (single episode, recurrent, mild, moderate,severe without psychotic features, severe with psychotic features,chronic, with catatonic features, with melancholic features, withatypical features, with postpartum onset, in partial remission, in fullremission), dysthymic disorder, adjustment disorder with depressed mood,adjustment disorder with mixed anxiety and depressed mood, premenstrualdysphoric disorder, minor depressive disorder, recurrent briefdepressive disorder, post-psychotic depressive disorder ofschizophrenia, a major depressive disorder associated with Parkinson'sdisease, and a major depressive disorder associated with dementia.

The term “anxiety disorders” refers to an excessive or inappropriatearoused state characterized by feelings of apprehension, uncertainty, orfear. Anxiety disorders have been classified according to the severityand duration of their symptoms and specific behavioral characteristics.Categories include: Generalized anxiety disorder (GAD), which islong-lasting and low-grade; Panic disorder, which has more dramaticsymptoms; Phobias; Obsessive-compulsive disorder (OCD); Post-traumaticstress disorder (PTSD); and Separation anxiety disorder.

The neurological disorder can be pain associated depression (PAD). Theterm “pain associated depression” refers to a depressive disordercharacterized by the co-morbidity of pain and atypical depression.Specifically, the pain can be chronic pain, neuropathic pain, or acombination thereof. Specifically, the pain associated depression caninclude atypical depression and chronic pain wherein the chronic painprecedes the atypical depression. Alternatively, the pain associateddepression can include atypical depression and chronic pain wherein theatypical depression precedes the chronic pain. The pain associateddepression can include atypical depression and neuropathic pain.

“Chronic pain” refers to pain that continues or recurs over a prolongedperiod of time (i.e., >3 mos.), caused by various diseases or abnormalconditions, such as rheumatoid arthritis. Chronic pain may be lessintense than acute pain. The person with chronic pain does not usuallydisplay increased pulse and rapid perspiration because the automaticreactions to pain cannot be sustained for long periods of time. Otherswith chronic pain may withdraw from the environment and concentratesolely on their affliction, totally ignoring their family, theirfriends, and external stimuli. See, Mosby's Medical, Nursing & AlliedHealth Dictionary, 5th Edition (1998).

Chronic pain can be selected from the group of lower back pain, atypicalchest pain, headache, pelvic pain, myofascial face pain, abdominal pain,and neck pain or chronic pain is caused by a disease or conditionselected from the group of arthritis, temporal mandibular jointdysfunction syndrome, traumatic spinal cord injury, multiple sclerosis,irritable bowel syndrome, chronic fatigue syndrome, premenstrualsyndrome, multiple chemical sensitivity, closed head injury,fibromyalgia, rheumatoid arthritis, diabetes, cancer, HIV, interstitialcystitis, migraine headache, tension headache, post-herpetic neuralgia,peripheral nerve injury, causalgia, post-stroke syndrome, phantom limbsyndrome, and chronic pelvic pain.

“Atypical depression” refers to a depressed affect, with the ability tofeel better temporarily in response to positive life effect (moodreactivity), plus two or more neurovegetative symptoms selected from thegroup of hypersomnia, increased appetite or weight gain, leadenparalysis, and a long standing pattern of extreme sensitivity toperceived interpersonal rejection; wherein the neurovegetative symptomsare present for more than about two weeks. It is appreciated that thoseof skill in the art recognize that the neurovegatative symptoms can bereversed compared to those found in other depressive disorders (e.g.,melancholic depression); hence the term “atypical.”

The term “mammal” refers to a class of vertebrate animals of more than15,000 species, including humans, distinguished by self-regulating bodytemperature, hair, and in the females, milk-producing mammae.Specifically, mammal can refer to a human. More specifically, mammal canrefer to a human adult, e.g., 18 years or older. More specifically,mammal can refer to an elderly human adult, e.g., 60 years or older.

The term “acute neurological disorder” refers to a neurologicaldisorder, as defined above, wherein the disorder has a rapid onset whichis followed by a short but severe course, including, but not limited to,Febrile Seizures, Guillain-Barré syndrome, stroke, and intracerebralhemorrhaging (ICH).

The term “chronic neurological disorder” refers to a neurologicaldisorder, as defined above, wherein the disorder lasts for a long periodof time (e.g., more than about 2 weeks; specifically, the chronicneurological disorder can continue or recur for more than about 4 weeks,more than about 8 weeks, or more than about 12 weeks) or is marked byfrequent recurrence, including, but not limited to, narcolepsy, chronicinflammatory demyelinating polyneuropathy, Cerebral palsy (CP),epilepsy, multiple sclerosis, dyslexia, Alzheimer's disease andParkinson's Disease.

The term “trauma” refers to any injury or shock to the body, as fromviolence or an accident. The term trauma also refers to any emotionalwound or shock, many of which may create substantial, lasting damage tothe psychological development of a person, often leading to neurosis.

The term “ischemic conditions” refers to any condition which results ina decrease in the blood supply to a bodily organ, tissue, or part causedby constriction or obstruction of the blood vessels, often resulting ina reduction of oxygen to the organ, tissue, or part.

The term “hypoxic conditions” refers to conditions in which theamount/concentration of oxygen in the air, blood or tissue is low(subnormal).

The term “painful neuropathy” or “neuropathy” refers to chronic painthat results from damage to or pathological changes of the peripheral orcentral nervous system. Peripheral neuropathic pain is also referred toas painful neuropathy, nerve pain, sensory peripheral neuropathy, orperipheral neuritis. With neuropathy, the pain is not a symptom ofinjury, but rather the pain is itself the disease process. Neuropathy isnot associated with the healing process. Rather than communicating thatthere is an injury somewhere, the nerves themselves malfunction andbecome the cause of pain.

“Neuropathic pain” refers to pain associated with inflammation ordegeneration of the peripheral nerves, cranial nerves, spinal nerves, ora combination thereof. The pain is typically sharp, stinging, orstabbing. The underlying disorder can result in the destruction ofperipheral nerve tissue and can be accompanied by changes in the skincolor, temperature, and edema. See, Mosby's Medical, Nursing & AlliedHealth Dictionary, 5th Edition (1998); and Stedman's Medical Dictionary,25th Edition (1990).

The term “diabetic neuropathy” refers to a peripheral nervedisorder/nerve damage caused by diabetes, including peripheral,autonomic, and cranial nerve disorders/damage associated with diabetes.Diabetic neuropathy refers to a common complication of diabetes mellitusin which nerves are damaged as a result of hyperglycemia (high bloodsugar levels).

The term “drug dependence” refers to habituation to, abuse of, and/oraddiction to a chemical substance. Largely because of psychologicalcraving, the life of the drug-dependent person revolves around the needfor the specific effect of one or more chemical agents on mood or stateof consciousness. The term thus includes not only the addiction (whichemphasizes the physiological dependence) but also drug abuse (in whichthe pathological craving for drugs seems unrelated to physicaldependence). Examples include, but are not limited to, alcohol, opiates,synthetic analgesics with morphine-like effects, barbiturates,hypnotics, sedatives, some antianxiety agents, cocaine,psychostimulants, marijuana, nicotine and psychotomimetic drugs.

The term “drug withdrawal” refers to the termination of drug taking.Drug withdrawal also refers to the clinical syndrome of psychological,and, sometimes physical factors that result from the sustained use of aparticular drug when the drug is abruptly withdrawn. Symptoms arevariable but may include anxiety, nervousness, irritability, sweating,nausea, vomiting, rapid heart rate, rapid breathing, and seizures.

The term “drug addiction” or dependence is defined as having one or moreof the of the following signs: a tolerance for the drug (needingincreased amounts to achieve the same effect), withdrawal symptoms,taking the drug in larger amounts than was intended or over a longerperiod of time than was intended, having a persistent desire to decreaseor the inability to decrease the amount of the drug consumed, spending agreat deal of time attempting to acquire the drug, or continuing to usethe drug even though the person knows there are reoccurring physical orpsychological problems being caused by the drug.

In one embodiment, when treating drug withdrawal, dependence and/ortolerance, the MMP inhibitor is administered with an NMDAR antagonist(e.g., memantine).

The term “tardive dyskinesia” refers to a serious, irreversibleneurological disorder that can appear at any age. Tardive Dyskinesia,e.g., Tourette's syndrome, can be a side effect of long-term use ofantipsychotic/neuroleptic drugs. Symptoms can be hardly noticeable orprofound. Symptoms involve uncontrollable movement of various bodyparts, including the body trunk, legs, arms, fingers, mouth, lips, ortongue.

The term “movement disorder” refers to a group of neurological disordersthat involve the motor and movement systems, including, but are notlimited to, Ataxia, Parkinson's disease, Blepharospasm, AngelmanSyndrome, Ataxia Telangiectasia, Dysphonia, Dystonic disorders, Gaitdisorders, Torticollis, Writer's Cramp, Progressive Supranuclear Palsy,Huntington's Chorea, Wilson's Disease, Myoclonus, Spasticity, Tardivedyskinesia, Tics and Tourette syndrome and Tremors.

The term “cerebral infections that disrupt the blood-brain barrier”refers to infections of the brain or cerebrum that result in analteration in the effectiveness of the blood-brain barrier, eitherincreasing or decreasing its ability to prevent, for example, substancesand/or organisms from passing out of the bloodstream and into the CNS.

The term “the blood-brain barrier” refers to a semi-permeable cell layerof endothelial cells (interior walls) within capillaries of the centralnervous system (CNS). The blood-brain barrier prevents large molecules,immune cells, many potentially damaging substances, and foreignorganisms (e.g., viruses), from passing out of the bloodstream and intothe CNS (Brain and Spinal Cord). A dysfunction in the Blood-BrainBarrier may underlie in part the disease process in MS (multiplesclerosis).

The term “meningitis” refers to inflammation of the meninges of thebrain and the spinal cord, most often caused by a bacterial or viralinfection and characterized by fever, vomiting, intense headache, andstiff neck.

The term “meningoencephalitis” refers to inflammation of both the brainand meninges.

The term “stroke” refers to a sudden loss of brain function caused by ablockage or rupture of a blood vessel to the brain (resulting in thelack of oxygen to the brain), characterized by loss of muscular control,diminution or loss of sensation or consciousness, dizziness, slurredspeech, or other symptoms that vary with the extent and severity of thedamage to the brain, also called cerebral accident, or cerebrovascularaccident. The term “cerebral ischemia” (or “stroke”) also refers to adeficiency in blood supply to the brain, often resulting in a lack ofoxygen to the brain.

The term “hypoglycemia” refers to an abnormally low level of glucose inthe blood.

The term “cardiac arrest” refers to a sudden cessation of heartbeat andcardiac function, resulting in a temporary or permanent loss ofeffective circulation.

The term “spinal cord trauma” refers to damage to the spinal cord thatresults from direct injury to the spinal cord itself or indirectly bydamage to the bones and soft tissues and vessels surrounding the spinalcord. It is also called Spinal cord compression; Spinal cord injury; orCompression of spinal cord.

The term “head trauma” refers to a head injury of the scalp, skull, orbrain. These injuries can range from a minor bump on the skull to adevastating brain injury. Head trauma can be classified as either closedor penetrating. In a closed head injury, the head sustains a blunt forceby striking against an object. A concussion is a type of closed headinjury that involves the brain. In a penetrating head injury, an objectbreaks through the skull and enters the brain.

The term “perinatal hypoxia” refers to a lack of oxygen during theperinatal period (defined as the period of time occurring shortly beforeand after birth, variously defined as beginning with completion of thetwentieth to twenty eighth week of gestation and ending 7 to 28 daysafter birth).

The term “hypoglycemic neuronal damage” refers to neuronal damage, forexample, nerve damage, as a result of a hypoglycemic condition (anabnormally low level of glucose in the blood).

The term “epilepsy” refers to any of various neurological disorderscharacterized by sudden recurring attacks of motor, sensory, or psychicmalfunction with or without loss of consciousness or convulsiveseizures.

The term “Alzheimer's disease” refers to a disease marked by the loss ofcognitive ability, generally over a period of 10 to 15 years, andassociated with the development of abnormal tissues and protein depositsin the cerebral cortex (known as plaques and tangles).

The term “Huntington's disease” refers to a disease that is hereditaryin nature and develops in adulthood and ends in dementia. Morespecifically, Huntington's disease (HD) results from geneticallyprogrammed degeneration of brain cells, called neurons, in certain areasof the brain caused by a polyglutamine repeat in the DNA sequence of thegene encoding the protein huntingtin. This degeneration causesuncontrolled movements, loss of intellectual faculties, and emotionaldisturbance.

The term “Parkinsonism” refers to a disorder similar to Parkinson'sdisease, but which is caused by the effects of a medication, a differentneurodegenerative disorder or another illness. The term “parkinsonism”also refers to any condition that causes any combination of the types ofmovement abnormalities seen in Parkinson's disease by damaging ordestroying dopamine neurons in a certain area of the brain.

The term “amyotrophic lateral sclerosis” (ALS), also called Lou Gehrig'sdisease and Motor Neuron Disease, refers to a progressive, fatalneurological disease. The disorder belongs to a class of disorders knownas motor neuron diseases. ALS occurs when specific nerve cells in thebrain and spinal cord that control voluntary movement graduallydegenerate (usually the “upper” (in the cerebrocortex) and “lower” (inthe spinal cord) motor neurons, although some variants known as primarylateral sclerosis, apparently representing a separate disease, affectonly the upper motor neurons). The loss of these motor neurons causesthe muscles under their control to weaken and waste away, leading toparalysis. ALS manifests itself in different ways, depending on whichmuscles weaken first. Symptoms may include tripping and falling, loss ofmotor control in hands and arms, difficulty speaking, swallowing and/orbreathing, persistent fatigue, and twitching and cramping, sometimesquite severely. Upper motor neuron variants (e.g., primary lateralsclerosis) are also included.

The term “glaucoma” refers to any of a group of eye diseasescharacterized by abnormally high intraocular fluid pressure, damagedoptic disk, hardening of the eyeball, and partial to complete loss ofvision. The retinal ganglion cells are lost in glaucoma. Some variantsof glaucoma have normal intraocular pressure (known also as low tensionglaucoma).

The term “retinal ischemia” refers to a decrease in the blood supply tothe retina.

The term “ischemic optic neuropathy” refers to a condition that usuallypresents with sudden onset of unilaterally reduced vision. The conditionis the result of decreased blood flow to the optic nerve (ischemia).There are two basic types: arteritic and non-arteritic ischemic opticneuropathy. Non-arteritic ischemic optic neuropathy is generally theresult of cardiovascular disease. Those patients at greatest risk have ahistory of high blood pressure, elevated cholesterol, smoking, diabetes,or combinations of these. Arteritic ischemic optic neuropathy is acondition caused by the inflammation of vessels supplying blood to theoptic nerve, known as temporal arteritis. This condition usuallypresents with sudden and severe vision loss in one eye, pain in the jawwith chewing, tenderness in the temple area, loss of appetite, and ageneralized feeling of fatigue or illness.

The term “macular degeneration” refers to the physical disturbance ofthe center of the retina called the macula. The macula is the part ofthe retina which is capable of our most acute and detailed vision.Macular degeneration is the leading cause of legal blindness in peopleover age 55 (legal blindness means that a person can see 20/200 or lesswith eyeglasses.) Even with a loss of central vision, however, colorvision and peripheral vision may remain clear. Vision loss usuallyoccurs gradually and typically affects both eyes at different rates.

As used herein a “demyelinating disorder” refers to a medical conditionwhere the myelin sheath is damaged. The myelin sheath surrounds nervesand is responsible for the transmission of impulses to the brain. Damageto the myelin sheath may result in muscle weakness, poor coordinationand possible paralysis. Examples of demyelinating disorders includeMultiple Sclerosis (MS), optic neuritis, transverse neuritis andGuillain-Barre Syndrome (GBS). In one embodiment, when treating ademyelinating disorder, an MMP inhibitor is administered with an NMDARantagonist (e.g., memantine) or with (3-interferon isoforms, copaxone orAntegren (natalizumab). Recently, it has been noted that underlyingneuronal damage can occur in demyelinating conditions such as MS, andtherefore useful drugs may also protect the neurons instead or inaddition to the myelin.

The term “multiple sclerosis” refers to a chronic disease of the centralnervous system, which predominantly affects young adults. Viral andautoimmune etiologies are postulated. Genetic and environmental factorsare known to contribute to MS, but a specific cause for this disease isnot yet identified. Pathologically, MS is characterized by the presenceof areas of demyelination and T-cell predominant perivascularinflammation in the brain white matter. Some axons may be spared fromthese pathological processes. The disease begins most commonly withacute or subacute onset of neurologic abnormalities. Initial andsubsequent symptoms may dramatically vary in their expression andseverity over the course of the disease, that usually lasts for manyyears. Early symptoms may include numbness and/or paresthesia, mono- orparaparesis, double vision, optic neuritis, ataxia, and bladder controlproblems. Subsequent symptoms also include more prominent upper motorneuron signs, i.e., increased spasticity, increasing para- orquadriparesis. Vertigo, incoordination and other cerebellar problems,depression, emotional lability, abnormalities in gait, dysarthria,fatigue and pain are also commonly seen.

The term “sequelae of hyperhomocystinemia” refers to a conditionfollowing as a consequence hyperhomocystinemia, meaning elevated levelsof homocysteine.

The term “convulsion” refers to a violent involuntary contraction orseries of contractions of the muscles.

The term “pain” refers to an unpleasant sensation associated with actualor potential tissue damage, and mediated by specific nerve fibers to thebrain where its conscious appreciation may be modified by variousfactors. See, Mosby's Medical, Nursing & Allied Health Dictionary,5^(th) Ed. Ed. (1998); and Stedman's Medical Dictionary, 25^(th) Ed.(1990).

The term “anxiety” refers to a state of apprehension, uncertainty,and/or fear resulting from the anticipation of a realistic or fantasizedthreatening event or situation, often impairing physical andpsychological functioning.

The term “schizophrenia” refers to any of a group of psychotic disordersusually characterized by withdrawal from reality, illogical patterns ofthinking, delusions, and hallucinations, and accompanied in varyingdegrees by other emotional, behavioral, or intellectual disturbances.Schizophrenia is associated with dopamine imbalances in the brain anddefects of the frontal lobe and is caused by genetic, other biological,and/or psychosocial factors.

The term “muscle spasm” refers to an often painful involuntary muscularcontraction

The term “migraine headache” refers to a severe, debilitating headacheoften associated with photophobia and blurred vision.

The term “urinary incontinence” refers to the inability to control theflow of urine and involuntary urination.

The term “nicotine withdrawal” refers to the withdrawal from nicotine,an addictive drug found in tobacco, which is characterized by symptomsthat include headache, anxiety, nausea and a craving for more tobacco.Nicotine creates a chemical dependency, so that the body develops a needfor a certain level of nicotine at all times. Unless that level ismaintained, the body will begin to go through withdrawal. For tobaccousers trying to quit, symptoms of withdrawal from nicotine areunpleasant and stressful, but temporary. Most withdrawal symptoms peak48 hours after one quits and are completely gone in six months.

The term “opiate tolerance” can be explained, at least in part, as ahomeostatic response that reduces the sensitivity of the system tocompensate for continued exposure to high levels of, for example,morphine or heroin. When the drug is stopped, the system is no longer assensitive to the soothing effects of the enkephalin neurons and the painof withdrawal is produced.

The term “opiate withdrawal” refers to an acute state caused bycessation or dramatic reduction of use of opiate drugs that has beenheavy and prolonged (several weeks or longer). Opiates include heroin,morphine, codeine, Oxycontin, Dilaudid, methadone, and others. Thereaction frequently includes sweating, shaking, headache, drug craving,nausea, vomiting, abdominal cramping, diarrhea, inability to sleep,confusion, agitation, depression, anxiety, and other behavioral changes.

The term “emesis” refers to the act of vomiting.

The term “brain edema” refers to an excessive accumulation of fluid in,on, around and/or in relation to the brain.

The term “AIDS induced dementia” or “HIV-associated dementia” refers todementia (deterioration of intellectual faculties, such as memory,concentration, and judgment, resulting from an organic disease or adisorder of the brain) induced by AIDS (Acquired ImmunodeficiencySyndrome—an epidemic disease caused by an infection by humanimmunodeficiency virus (HIV-1, HIV-2), a retrovirus that causes immunesystem failure and debilitation and is often accompanied by infectionssuch as tuberculosis).

The term “HIV-related neuropathy” refers to a neuropathy in a mammalinfected with HIV were the neuropathy is caused by infections such asCMV or other viruses of the herpes family. Neuropathy is the name givento a group of disorders whose symptoms may range from a tinglingsensation or numbness in the toes and fingers to paralysis. Neuropathymight more accurately be called “neuropathies” because there are severaltypes and can be painful.

The term “ocular damage” refers to any damage to the eyes or in relationto the eyes.

The term “retinopathy” refers to any pathological disorder of theretina.

The term “cognitive disorder” refers to any cognitive dysfunction, forexample, disturbance of memory (e.g., amnesia) or learning.

The term “neuronal injury associated with HIV infection” refers todamage/injury of nerve cells caused either directly or indirectly byinfection with HIV.

The term “dysfunction in cognition, movement and sensation” refers toabnormal or impaired functioning in cognition (mental process ofknowing, including aspects such as awareness, perception, reasoning, andjudgment), movement or sensation.

Any of the above diseases, disorders, or conditions can be treated byadministering a compound or composition that includes a compounddescribed herein to treat the disease, disorder, or condition byinhibiting matrix a metalloproteinase.

The following Examples illustrate the above invention and should not beconstrued as to narrow its scope. One skilled in the art will readilyrecognize that the Examples suggest many other ways in which theinvention could be practiced. It should be understood that numerousvariations and modifications may be made while remaining within thescope of the invention.

EXAMPLES Example 1 Preparation of MMP Inhibitors and Prodrugs

The p-aminophenoxybenzene scaffold was assembled by the methodologydeveloped by Ikejiri et al. (J. Biol. Chem. 2005, 280, 33992-34002).This methodology includes the coupling of 1-fluoro-4-nitrobenzene (1)and 4-(allylthio)phenol (2) under basic condition, followed by reductionof the nitro group to amine over elemental zinc in acetic acid. Theresulting amine 3 was treated with di-tert-butyl dicarbonate to give theBoc protected compound 4. The Boc group was chosen as the amineprotecting group because the sulfonylmethylthiirane is relatively stableunder acidic condition that is used for the removal of Boc at the end ofthe synthesis (see transformation of 5 to 6). The rest of thetransformations, including oxidation to sulfone, epoxide formation usingm-chloroperbenzoic acid, and thiirane conversion using thiourea, wereperformed by the methodology developed by the Mobashery group earlier(Org. Lett. 2005, 7, 4463-4465; J. Org. Chem. 2004, 69, 3572-3573).Removal of the Boc group in compound 5 was carried out in the presenceof 4 N HCl in 1,4-dioxane at room temperature for 24 hours to yieldcompound 6 as the HCl salt in 82%.

Syntheses of amino acid conjugates of benzamine (6) and phenol (7) asprodrugs of gelatinase inhibitors are outlined in Scheme 2. Compound 7,prepared according to the literature (Chem. Biol. & Drug Des. 2009, 73,189-202), was acylated with Boc-protected N-hydroxysuccinimide esters ofamino acids (Gly, L-Lys, L-Glu, L-Arg, and L-Arg-L-Arg) in the presenceof 4-(dimethylamino)pyridine (DMAP) to give the ester 8. The Boc groupin compound 8, in turn, was readily removed by treatment with 4 N HCl in1,4-dioxane to result in the ester prodrug 9. The acid treatment forremoval of the Boc group in the presence of thiirane works well, asdescribed in Scheme 1 for the synthesis of compound 6.

When the compound 6 was subjected to the same acylation conditions, thedesired amide bond was not formed, instead, it gave only recovery of thetwo starting materials. Boc-protected amino acid was activated to mixedanhydride by treatment of isobutyl chloroformate in the presence ofN-methylmorpholine, which was allowed to react with compound 6 to givethe desired amide linkage. The removal of Boc group in compound 10 wascarried out by acid treatment resulting in the amide prodrug 11.

When compounds 6 and 7 were treated with p-nitrophenyl carbonate e s ofDAMP, the desired prodrugs 13 and 14 were accessed.

TABLE 1. Various Specific Prodrugs.

X Compound No Compound No Gly 9a 11a Lys 9b 11b Glu 9c 11c Arg 9d 11dArg-Arg 9e 11e dioxolone* 13 14

Experimental Procedures t-Butyl [4-(4-allylthiophenoxy)phenyl]carbamate(4)

Compound 3 (10.3 g, 40.0 mmol), which was prepared by a literaturemethod (J. Biol. Chem. 2005, 280, 33992-34002), was dissolved in amixture of MeOH and triethylamine (7:1, 80 mL) and di-t-butyldicarbonate(17.5 g, 80 mmol) was added. The resulting solution was stirred for 2 hat 60° C. and concentrated under reduced pressure. The crude materialwas purified by column chromatography on silica gel to give the titlecompound (11.7 g, 82%). ¹H NMR (600 MHz, CDCl₃) δ 1.53 (s, 9H), 3.48 (d,J=6.7 Hz, 2H), 4.96-5.09 (m, 2H), 5.86 (m, J=16.7, 10.3 Hz, 1H), 6.47(br. s, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 7.24-7.39(m, 4H); ¹³C NMR (151 MHz, CDCl₃) δ 28.5, 38.9, 80.7, 117.7, 118.6,120.3, 120.5, 128.9, 133.3, 134.0, 134.5, 152.2, 153.1, 157.4; HRMS-FAB(m/z): [M]⁺, calcd for C₂₀H₂₃NO₃S, 357.1399. found, 357.1402.

t-Butyl [4-(4-(thiiran-2-yl)methylsulfonylphenoxy)phenyl]carbamate (5)

To a solution of compound 4 (10.0 g, 28.0 mmol) in CH₂Cl₂ (100 mL) wasadded a solution of m-chloroperoxybenzoic acid (31.2 g, 140 mmol, 77%)in an ice-water bath. After 48 h, the suspension was filtered and thefiltrate was diluted with EtOAc and washed with 10% aqueous sodiumthiosulfate, followed by washes with saturated sodium bicarbonate andbrine. The organic layer was dried over MgSO₄ and was concentrated. Theproduct was purified by silica gel chromatography to yield the oxirane(7.4 g, 81%) with recovery of some of the allylsulfone derivative (2.1g, 19%). ¹H NMR (600 MHz, CDCl₃) δ 1.50 (s, 9H), 2.45 (dd, J=5.0, 1.2Hz, 1H), 2.79 (dd, J=4.4, 2.6 Hz, 1H), 3.24-3.34 (m, 3H), 6.85 (s, 1H),6.99 (d, J=8.8 Hz, 2H), 7.02 (d, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.84 (d,J=8.8 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 28.4, 46.0, 46.0, 59.7, 117.2,120.5, 121.3, 130.6, 132.2, 136.0, 149.8, 153.0, 163.4; HRMS-FAB (m/z):[M]⁺, calcd for C₂₀H₂₃NO₆S, 405.1246. found, 405.1230.

Thiourea (2.4 g, 31.5 mmol) was added to a solution of oxirane (6.0 g,14.8 mmol), obtained above, in a 1:1 mixture of methanol and CH₂Cl₂ (50mL). The reaction mixture was stirred at room temperature for 24 h. Thesolvent was removed under reduced pressure. The residue was partitionedbetween CH₂Cl₂ and water, the organic layer was washed with brine andwater, dried (MgSO₄) and the suspension was filtered. Evaporation ofsolvent gave the crude product, which was purified by columnchromatography on silica gel to give thiirane 5 (4.4 g, 72%). ¹H NMR(600 MHz, CDCl₃) δ 1.53 (s, 9H), 2.16 (dd, J=5.1, 1.6 Hz, 1H), 2.54 (dd,J=6.2, 1.2 Hz, 1H), 3.06 (dq, J=7.6, 5.7 Hz, 1H), 3.17 (dd, J=14.1, 7.9Hz, 1H), 3.53 (dd, J=14.1, 5.6 Hz, 1H), 6.61 (br. s, 1H), 7.06 (d, J=8.8Hz, 2H), 7.03 (d, J 8.8 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.8Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 24.5, 26.3, 28.5, 62.8, 81.0, 117.4,120.6, 121.4, 130.9, 131.8, 136.0, 150.0, 153.0, 163.6; HRMS-FAB (m/z):[M]⁺, calcd for C₂₀H₂₃NO₅S₂, 421.1018. found, 421.1009.

4-[4-((Thiiran-2-yl)methylsulfonyl)phenoxy]benzamine.HCl salt

The thiirane (4.0 g, 9.5 mmol) was dissolved in a 1:1 mixture of CH₂Cl₂and ethyl acetate (40 mL) and HCl (10 mL, 4 N in dioxane) was added. Thereaction mixture was stirred for 24 h and concentrated under reducedpressure. The resulting crude compound was triturated with diethyl etherand the product was obtained by filtration (2.8 g, 82%). ¹H NMR (500MHz, D₂O) δ 2.03 (d, J=4.8 Hz, 1H), 2.42 (d, J=6.4 Hz, 1H), 2.94 (m, J6.4, 6.4 Hz, 1H), 3.42 (dd, J=14.4, 6.4 Hz, 1H), 3.61 (dd, J=14.4, 6.4Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0Hz, 2H), 7.80 (d, J=8.0 Hz, 2H); ¹³C NMR (126 MHz, D₂O) δ 23.5, 26.0,61.4, 118.6, 121.9, 125.2, 126.8, 130.8, 131.1, 155.2, 162.5; HRMS-FAB(m/z): [M+H]⁺, calcd for C₁₅H₁₆NO₃S₂, 322.0572. found, 322.0569.

Syntheses of Ester Prodrugs (9)

Synthesis of the lysine prodrug (9b) is provided here as arepresentative example.

To a solution of 7 (0.20 g, 0.62 mmol) (prepared according to the methodof Stella and Nti-Addae; Adv. Drug Deliv. Rev. 2007, 59, 677-94) inCH₂Cl₂ (5 mL) was added N_(α),N_(ε)-di-Boc-L-lysine hydroxysuccinimideester (0.41 g, 0.93 mmol) at room temperature. 4-Dimethylamino-pyridine(76 mg, 0.62 mmol) was added and the reaction mixture was stirred for 3h at room temperature. After concentrating under reduced pressure, thecrude product was purified by column chromatography on silica gel togive the desired product (8b, 0.30 g, 74%). The ester (0.30 g, 0.46mmol) was dissolved in CH₂Cl₂ and ethyl acetate (1:1, 4 mL) and HCl (2mL, 4 N in dioxane) was added. The reaction mixture was stirred for 24 hand concentrated under reduced pressure. The resulting crude compoundwas triturated with diethyl ether and the product (9b) was obtained byfiltration (0.18 g, 75%).

Syntheses of amide prodrugs (11)

Synthesis of the lysine prodrug (11b) is provided as a representativeexample.

i-Butylchloroformate (83 μL, 0.53 mmol) was added to a mixture ofN_(α),N_(ε)-di-Boc-L-lysine dicyclohexylamine salt (0.28 g, 0.64 mmol)and N-methylmorpholine (140 μL, 1.3 mmol) in THF (4 mL) at −15° C. Afterstirring for 0.5 h at the same temperature, the suspension of 6 (0.19 g,0.53 mmol) and N-methylmorpholine (58 μL, 0.53 mmol) in THF (2 mL) wasadded to the reaction mixture. Stirring was continued for 1 h, whiletemperature was gradually increased to room temperature. The reactionmixture was diluted with CH₂Cl₂/water and layers were separated. Theaqueous layer was extracted and the combined organic layers were dried(MgSO₄) and evaporated. The crude material was purified by columnchromatography on silica gel to afford the desired product (10b, 0.21 g,64%). Amide (0.20 g, 0.30 mmol) was dissolved in CH₂Cl₂ and ethylacetate (1:1, 3 mL) and HCl (2 mL, 4 N in dioxane) was added. Thereaction mixture was stirred for 24 h and concentrated under reducedpressure. The resulting crude compound was triturated with diethyl etherand the product (11b) was obtained by filtration (0.11 g, 71%).

Spectral data of Gly ester prodrug compound 8a. ¹H NMR (500 MHz, CDCl₃)δ 1.48 (s, 9H), 2.17 (dd, J=5.0, 1.8 Hz, 1H), 2.55 (dd, J=6.2, 1.8 Hz,1H), 3.04-3.10 (m, 1H), 3.20 (dd, J=14.4, 7.8 Hz, 1H), 3.52 (dd, J=14.2,5.6 Hz, 1H), 4.19 (d, J=5.8 Hz, 2H), 7.11 (d, J=9.0 Hz, 2H), 7.12 (d, J8.8 Hz, 2H), 7.18 (d, J=9.0 Hz, 2H), 7.88 (d, J=9.0 Hz, 2H); ¹³C NMR(126 MHz, CDCl₃) δ 24.4, 26.2, 28.5, 42.7, 62.7, 80.5, 117.9, 121.5,123.3, 131.0, 132.4, 147.3, 152.6, 162.8, 169.3; HRMS-ESI (m/z): [M+H]⁺,calcd for C₂₂H₂₆N₂O₆S₂, 480.1145. found, 480.1145.

Compound 9a. ¹H NMR (500 MHz, D₂O) δ 2.17 (dd, J=5.2, 1.2 Hz, 1H), 2.56(d, J=6.2 Hz, 1H), 3.09 (quin, J=6.2 Hz, 1H), 3.57 (dd, J=14.6, 7.2 Hz,1H), 3.74 (dd, J=14.6, 6.4 Hz, 1H), 4.25 (s, 2H), 7.21-7.35 (m, 6H),7.93 (d, J=8.8 Hz, 2H); HRMS-ESI (m/z): [M+H]⁺, calcd for C₁₇H₁₈NO₅S₂,380.0621. found, 380.0597.

Spectral data of Lys ester prodrug compound 8b. ¹H NMR (500 MHz, CDCl₃)δ 1.45 (s, 9H), 1.47 (s, 9H), 1.52 (m, 2H), 1.56 (m, 4H), 1.85 (m, 1H),1.99 (m, 1H), 2.17 (dd, J=5.2, 1.8 Hz, 1H), 2.55 (dd, J=6.2, 1.8 Hz,1H), 3.07 (m, 1H), 3.17 (m, 2H), 3.19 (dd, J=14.2, 7.8 Hz, 1H), 3.53(dd, J=14.2, 5.6 Hz, 1H), 4.49 (m, 1H), 4.61 (m, 1H), 5.23 (d, J=7.4 Hz,1H), 7.10 (d, J=9.0 Hz, 1H), 7.11 (d, J=8.8 Hz, 2H), 7.17 (d, J=9.0 Hz,1H); ¹³C NMR (126 MHz, CDCl₃) δ 22.7, 24.4, 26.3, 28.5, 28.6, 29.9,32.1, 40.1, 53.8, 62.8, 79.5, 80.3, 81.3, 117.9, 121.6, 123.4, 131.0,132.4, 147.6, 152.6, 162.9, 171.8; HRMS-ESI (m/z): [M+H]⁺, calcd forC₃₁H₄₃N₂O₉S₂, 651.2404. found, 651.2414.

Compound 9b. ¹H NMR (500 MHz, 10% CDCl₃ in CD₃OD) δ 1.62-1.84 (m, 4H),2.05-2.26 (m, 2H), 2.14 (dd, J=5.0, 1.4 Hz, 1H), 2.52 (dd, J=6.3, 1.1Hz, 1H), 3.01 (t, J=7.6 Hz, 2H), 3.06 (m, 1H), 3.46 (dd, J=14.6, 7.0 Hz,1H), 3.54 (t, J=6.6 Hz, 1H), 4.40 (t, J=6.5 Hz, 1H), 7.19 (d, J=9.0 Hz,2H), 7.23 (d, J=9.0 Hz, 2H), 7.32 (d, J=9.2 Hz, 2H), 7.94 (d, J=9.0 Hz,2H); HRMS-ESI (m/z): [M+H]⁺, calcd for C₂₁H₂₇N₂O₅S₂, 451.1356. found,541.1298.

Spectral data of Glu ester prodrug compound 8c. ¹H NMR (500 MHz, CDCl₃)δ 1.45 (s, 18H), 2.09 (m, 1H), 2.15 (dd, J=5.2, 1.8 Hz, 1H), 2.29 (m,1H), 2.43 (q, J=7.4 Hz, 2H), 2.52 (dd, J=6.2, 1.8 Hz, 1H), 3.05 (m, 1H),3.18 (dd, J=14.4, 7.8 Hz, 1H), 3.51 (dd, J=14.4, 5.8 Hz, 1H), 4.52 (m,1H), 5.26 (d, J=8.2 Hz, 1H), 7.08 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz,2H), 7.17 (d, J=9.2 Hz, 2H), 7.86 (d, J=9.0 Hz, 2H); ¹³C NMR (126 MHz,CDCl₃) δ 24.4, 26.2, 27.3, 28.2, 28.4, 31.7, 53.5, 62.7, 80.4, 81.1,117.9, 121.4, 123.3, 130.9, 132.3, 147.5, 152.5, 155.6, 162.8, 171.3,172.1; HRMS-ESI (m/z): [M+H]⁺, calcd for C₂₉H₃₈NO₉S₂, 608.1982. found,608.1981.

Compound 9c. ¹H NMR (500 MHz, 10% CDCl₃ in CD₃OD) δ 2.14 (dd, J=5.1, 1.3Hz, 1H), 2.37 (m, 2H), 2.52 (dd, J=6.2, 1.0 Hz, 1H), 2.68 (td, J=7.1,1.6 Hz, 2H), 3.05 (quin, J=6.2 Hz, 1H), 3.44 (dd, J=14.4, 7.0 Hz, 1H),3.54 (dd, J=14.4, 6.4 Hz, 1H), 4.43 (t, J=6.8 Hz, 1H), 7.19 (d, J=8.8Hz, 2H), 7.22 (d, J=9.2 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 7.93 (d, J=9.0Hz, 2H); HRMS-ESI (m/z): [M+H]⁺, calcd for C₂₀H₂₂NO₇S₂, 452.0832. found,452.0769.

Spectral data of Arg ester prodrug compound 8d. ¹H NMR (500 MHz, CDCl₃)δ 1.46 (s, 9H), 1.50 (s, 9H), 1.77 (m, 1H), 1.94 (m, 1H), 2.13 (dd,J=5.0, 1.6 Hz, 1H), 2.51 (dd, J=6.2, 1.6 Hz, 1H), 3.03 (m, 1H), 3.17(dd, J=14.2, 7.8 Hz, 1H), 3.49 (dd, J=14.2, 5.6 Hz, 1H), 3.84 (m, 1H),3.96 (m, 1H), 4.50 (m, 1H), 5.83 (d, J=8.2 Hz, 1H), 7.07 (d, J=9.0 Hz,2H), 7.08 (d, J=8.8 Hz, 2H), 7.14 (d, J=9.0 Hz, 1H), 7.85 (d, J=9.0 Hz,2H); ¹³C NMR (126 MHz, CDCl₃) δ 24.3, 26.2, 28.1, 28.3, 28.5, 44.1,53.5, 60.5, 62.7, 84.1, 117.8, 121.4, 123.4, 130.9, 132.3, 147.7, 152.4,155.0, 155.6, 160.6, 162.8, 163.6, 171.2; HRMS-ESI (m/z): [M+H]⁺, calcdfor C₃₆H₅₁N₄O₁₁S₂, 779.2990. found, 779.3001.

Compound 9d. ¹H NMR (500 MHz, 10% CDCl₃ in CD₃OD) δ 1.78-2.26 (m, 4H),2.14 (dd, J 5.1, 1.3 Hz, 1H), 2.52 (dd, J=6.2, 0.8 Hz, 1H), 3.04 (quin,J=6.2 Hz, 1H), 3.27 (m, 2H), 3.43 (dd, J 14.4, 7.0 Hz, 1H), 3.52 (dd,J=14.8, 6.6 Hz, 1H), 4.39 (t, J=6.5 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H),7.21 (d, J=9.0 Hz, 1H), 7.30 (d, J=9.0 Hz, 2H), 7.92 (d, J=8.8 Hz, 2H);HRMS-ESI (m/z): [M+H]⁺, calcd for C₂₁H₂₇N₄O₅S₂, 479.1417. found,479.1423.

Spectral data of Arg-Arg ester prodrug compound 8e. ¹H NMR (500 MHz,CDCl₃) δ 1.39-1.53 (m, 45H), 1.54-2.11 (m, 8H), 2.16 (dd, J=5.2, 1.4 Hz,1H), 2.54 (d, J=5.2 Hz, 1H), 3.06 (m, 1H), 3.19 (dd, J=14.2, 7.8 Hz,1H), 3.47 (dd, J=12.8, 7.0 Hz, 2H), 3.52 (dd, J=14.4, 5.6 Hz, 1H),3.74-3.95 (m, 2H), 4.32 (dd, J=14.8, 6.4 Hz, 1H), 4.77 (m, 1H), 5.92 (d,J=7.8 Hz, 1H), 7.07-7.12 (m, 4H), 7.16 (d, J=9.0 Hz, 2H), 7.33 (d, J=7.6Hz, 1H), 7.87 (d, J=8.8 Hz, 2H), 8.38 (t, J=4.9 Hz, 1H), 9.30 (br. s,2H), 11.50 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 24.4, 24.9, 25.6, 26.2,28.2, 28.2, 28.5, 28.6, 29.3, 40.4, 44.1, 52.5, 54.3, 62.8, 79.5, 80.2,83.4, 83.5, 84.2, 117.9, 121.5, 121.5, 123.4, 130.8, 131.0, 132.3,147.5, 152.5, 153.4, 155.0, 156.4, 160.8, 160.9, 162.9, 163.7, 170.6,172.7; HRMS-ESI (m/z): [M+H]⁺, calcd for C₅₂H₇₉N₈O₁₆S₂, 1135.5050.found, 1135.5039.

Compound 9e. ¹H NMR (500 MHz, 10% CDCl₃ in CD₃OD) δ 1.71-2.23 (m, 8H),2.16 (dd, J=5.0, 1.2 Hz, 1H), 2.54 (dd, J=6.2, 0.8 Hz, 1H), 3.03-3.10(m, 1H), 3.23-3.32 (m, 4H), 3.47 (dd, J=14.4, 7.0 Hz, 1H), 3.54 (dd,J=14.2, 6.4 Hz, 1H), 4.16 (t, J=6.4 Hz, 1H), 4.72 (dd, J=9.1, 4.5 Hz,1H), 7.15-7.23 (m, 4H), 7.25 (d, J=9.0 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H);HRMS-ESI (m/z): [M+H]⁺, calcd for C₂₇H₃₉N₈O₆S₂, 635.2428. found,635.2449.

Spectral data of Gly amide prodrug compound 10a. ¹H NMR (500 MHz, CDCl₃)δ 1.37 (s, 9H), 2.05 (dd, J=5.2, 1.8 Hz, 1H), 2.44 (dd, J=6.2, 1.8 Hz,1H), 2.94 (m, 1H), 3.14 (dd, J=14.4, 7.6 Hz, 1H), 3.41 (dd, J=14.4, 6.0Hz, 1H), 3.80 (d, J=5.2 Hz, 2H), 3.82 (s, 1H), 6.96 (d, J=15.2 Hz, 2H),6.98 (d, J=15.4 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H);¹³C NMR (126 MHz, CDCl₃) δ 24.0, 25.9, 28.2, 44.2, 62.5, 80.4, 117.4,121.0, 121.8, 130.7, 131.4, 150.7, 163.3, 168.3, 172.9; HRMS-ESI (m/z):[M+Na]⁺, calcd for C₂₂H₂₆N₂O₆S₂Na, 501.1124. found, 501.1112.

Compound 11a. ¹H NMR (500 MHz, 10% CDCl₃ in CD₃OD) δ 2.14 (dd, J=5.2,1.6 Hz, 1H), 2.51 (dd, J=6.3, 1.5 Hz, 1H), 3.04 (m, J=7.0, 5.2 Hz, 1H),3.42 (dd, J=14.4, 7.0 Hz, 1H), 3.53 (dd, J=14.4, 6.4 Hz, 1H), 4.14 (s,2H), 7.17 (d, J=9.0, 2.0, 1.8 Hz, 1H), 7.20 (d, J=9.2 Hz, 2H), 7.29 (d,J 9.2 Hz, 2H), 7.92 (d, J=9.2 Hz, 1H); HRMS-ESI (m/z): [M+H]⁺, calcd forC₁₇H₁₉N₂O₄S₂, 379.0781. found, 379.0805.

Spectral data of Lys amide prodrug compound 10b. ¹H NMR (500 MHz, CDCl₃)δ 1.41 (s, 9H), 1.43 (s, 9H), 2.02 (s, 3H), 2.13 (dd, J=5.0, 1.6 Hz,1H), 2.50 (dd, J=6.2, 1.6 Hz, 1H), 3.02 (m, 1H), 3.09 (m, 2H), 3.16 (dd,J=14.4, 7.8 Hz, 1H), 3.50 (dd, J=14.4, 5.8 Hz, 1H), 4.28 (m, 1H), 4.75(m, 1H), 5.53 (d, J=7.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.6Hz, 2H), 7.55 (d, J 8.8 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H); ¹³C NMR (126MHz, CDCl₃) δ 24.4, 26.2, 28.5, 28.6, 29.8, 31.9, 39.8, 55.3, 62.7,79.3, 80.5, 117.4, 121.1, 121.7, 130.8, 131.8, 135.6, 150.5, 156.4,156.6, 163.3, 171.2; HRMS-ESI (m/z): [M+Na]⁺, calcd for C₃₁H₄₃N₃O₈S₂Na,672.2384. found, 672.2393.

Compound 11b. ¹H NMR (500 MHz, 10% CDCl₃ in CD₃OD) δ 1.59-1.86 (m, 4H),2.06-2.25 (m, 2H), 2.14 (dd, J=5.2, 1.4 Hz, 1H), 2.52 (dd, J=6.4, 1.4Hz, 1H), 3.00 (t, J=7.6 Hz, 2H), 3.05 (m, 1H), 3.45 (dd, J=14.4, 6.8 Hz,1H), 3.53 (dd, J=14.6, 6.6 Hz, 1H), 4.39 (t, J=6.5 Hz, 1H), 7.18 (d,J=8.8 Hz, 2H), 7.22 (d, J=9.2 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 7.93 (d,J=9.0 Hz, 2H); HRMS-ESI (m/z): [M+H]⁺, calcd for C₂₁H₂₈N₃O₄S₂, 450.1516.found, 450.1485.

Spectral data of Glu amide prodrug compound 10c. ¹H NMR (500 MHz, CDCl₃)δ 1.47 (s, 9H), 1.49 (s, 9H), 2.00 (m, 1H), 2.17 (dd, J=5.2, 1.8 Hz,1H), 2.41 (m, 1H), 2.56 (m, 2H), 3.07 (m, 1H), 3.18 (dd, J=14.3, 7.9 Hz,1H), 3.54 (dd, J=14.1, 5.5 Hz, 1H), 4.27 (m, 1H), 7.07 (d, J=8.6 Hz,2H), 7.08 (d, J=9.0 Hz, 2H), 7.61 (d, J=9.0 Hz, 1H), 7.86 (d, J=9.0 Hz,1H); ¹³C NMR (126 MHz, CDCl₃) δ 24.5, 26.3, 28.2, 28.5, 37.1, 51.5,62.8, 82.3, 117.6, 121.3, 121.9, 130.9, 131.9, 135.2, 151.0, 163.3,169.3, 171.7; HRMS-ESI (m/z): [M+Na]⁺, calcd for C₂₉H₃₈N₂O₈S₂Na,629.1962. found, 629.1969.

Compound 11c. ¹H NMR (500 MHz, 10% CDCl₃ in CD₃OD) δ 2.32 (m, 1H), 2.42(m, 1H), 2.51 (dd, J=6.2, 1.4 Hz, 1H), 2.68 (dt, J=7.2, 6.8, 2.0 Hz,2H), 3.04 (m, 1H), 3.44 (dd, J=14.4, 7.0 Hz, 1H), 3.53 (dd, J=14.4, 6.4Hz, 1H), 4.43 (t, J=6.8 Hz, 1H), 4.87 (s, 10H), 7.19 (d, J=9.2 Hz, 2H),7.22 (d, J=9.2 Hz, 2H), 7.32 (d, J=9.2 Hz, 2H); HRMS-ESI (m/z): [M+H]⁺,calcd for C₂₀H₂₃N₂O₆S₂, 451.0992. found, 451.1004.

Spectral data of Arg amide prodrug compound 10d. ¹H NMR (500 MHz, CDCl₃)δ 1.38 (s, 9H), 1.48 (s, 9H), 1.53 (s, 9H), 1.59-1.96 (m, 4H), 2.16 (dd,J=5.2, 1.8 Hz, 1H), 2.54 (dd, J=6.2, 1.6 Hz, 1H), 3.06 (m, 1H), 3.17(dd, J=14.2, 8.0 Hz, 1H), 3.53 (dd, J=14.2, 5.6 Hz, 1H), 3.72 (m, 1H),4.12 (s, 1H), 4.55 (m, 1H), 5.99 (d, J=8.2 Hz, 1H), 7.05 (d, J=9.0 Hz,2H), 7.07 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.85 (d, J=9.0 Hz,2H), 9.13 (br. s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 24.5, 24.7, 26.3,28.2, 28.6, 29.3, 44.1, 54.0, 62.8, 84.6, 117.6, 121.2, 123.4, 130.9,132.0, 135.1, 151.3, 155.0, 161.3, 163.2, 163.4, 171.1; HRMS-ESI (m/z):[M+H]⁺, calcd for C₃₆H₅₂N₅O₁₀S₂, 778.3150. found, 778.3154.

Compound 11d. ¹H NMR (500 MHz, 10% CDCl₃ in CD₃OD) δ 1.71-2.11 (m, 4H),2.16 (d, J=5.2 Hz, 1H), 2.54 (dd, J=6.2, 1.2 Hz, 1H), 3.06 (quin, J=6.2Hz, 1H), 3.29 (m, 1H), 3.45 (m, 2H), 3.54 (dd, J=14.6, 6.4 Hz, 1H), 4.14(m, 1H), 7.15 (d, J=9.0 Hz, 2H), 7.15 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0Hz, 2H), 7.92 (d, J=8.8 Hz, 2H); HRMS-ESI (m/z): [M+H]⁺, calcd forC₂₁H₂₈N₅O₄S₂, 478.1577. found, 478.1580.

Spectral data of Arg-Arg amide prodrug compound 10e. ¹H NMR (500 MHz,CDCl₃) δ 1.40-1.54 (5×s, 45H), 1.46-1.90 (m, 8H), 2.16 (dd, J=5.2, 1.8Hz, 1H), 2.53 (dd, J=6.2, 1.4 Hz, 1H), 3.05 (m, 1H), 3.16 (dd, J=14.2,7.8 Hz, 1H), 3.39 (m, 1H), 3.53 (dd, J=14.2, 5.6 Hz, 1H), 3.55 (m, 2H),3.82 (t, J=6.8 Hz, 2H), 4.28 (dd, J=13.8, 6.4 Hz, 1H), 4.59 (q, J=7.4Hz, 1H), 6.10 (d, J=7.4 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 7.05 (d, J=8.8Hz, 2H), 7.22 (d, J=6.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.84 (d, J=9.0Hz, 2H), 8.41 (t, J=5.6 Hz, 1H), 8.84 (s, 1H), 9.26 (br. s, 1H), 9.35(br. s, 1H), 11.47 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 22.8, 24.5, 25.4,26.1, 26.2, 28.2, 28.2, 28.4, 28.4, 28.6, 29.2, 31.8, 34.8, 40.1, 44.1,53.8, 55.0, 62.8, 79.6, 80.6, 83.4, 84.3, 117.5, 121.2, 122.5, 130.9,131.8, 135.4, 150.9, 153.4, 154.9, 156.6, 160.8, 163.4, 163.4, 163.5,169.6; HRMS-ESI (m/z): [M+H]⁺, calcd for C₅₂H₈₀N₉O₁₅S₂, 1134.5210.found, 1134.5215.

Compound 11e. ¹H NMR (500 MHz, 10% CDCl₃ in CD₃OD) δ 1.68-2.05 (m, 8H),2.13 (dd, J=5.1, 1.3 Hz, 1H), 2.51 (dd, J=6.2, 1.0 Hz, 1H), 3.17 (m,1H), 3.22-3.28 (m, 4H), 3.42 (dd, J=14.6, 7.0 Hz, 1H), 3.50 (dd, J=14.0,7.0 Hz, 1H), 4.10 (t, J=6.3 Hz, 1H), 4.52 (dd, J=8.7, 5.1 Hz, 1H), 7.10(t, J=8.9 Hz, 4H), 7.66 (d, J=9.0 Hz, 2H), 7.89 (d, J=9.0 Hz, 2H);HRMS-ESI (m/z): [M+H]⁺, calcd for C₂₇H₄₀N₉O₅S₂, 634.2588. found,634.2585.

Syntheses of Dioxolone Prodrugs

A solution of compound 7 (0.10 g, 0.31 mmol) and5-methyl-2-oxo-1,3-dioxol-4-en-4-yl)methyl p-nitrophenyl carbonate (0.10g, 0.34 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature for 2 h.The reaction mixture was concentrated and after column chromatography onsilica gel, the desired product 13 was obtained (0.11 g, 71%). ¹H NMR(500 MHz, CDCl₃) δ 2.15 (dd, J=5.2, 1.8 Hz, 1H), 2.21 (s, 6H), 2.52 (dd,J=6.2, 1.4 Hz, 1H), 3.04 (m, J=7.0, 6.0 Hz, 1H), 3.20 (dd, J=14.3, 7.7Hz, 1H), 3.49 (dd, J=14.3, 5.9 Hz, 1H), 5.01 (s, 2H), 7.11 (d, J=9.2 Hz,2H), 7.10 (d, J=9.0 Hz, 2H), 7.24 (d, J=9.2 Hz, 2H), 7.87 (d, J=9.0 Hz,2H); ¹³C NMR (126 MHz, CDCl₃) δ 9.6, 24.3, 26.2, 57.9, 62.7, 77.4,118.0, 121.5, 122.8, 130.9, 132.5, 132.6, 141.3, 147.7, 151.9, 152.8,153.4, 162.6; HRMS-ESI (m/z): [M+H]⁺, calcd for C₂₁H₁₉O₉S₂, 479.0465.found, 479.0472.

The synthesis of carbamate 14 was carried out in an analogous manner tocarbonate 13 using 6 in the presence of 4-(dimethylamino)pyridine. ¹HNMR (500 MHz, CDCl₃) δ 2.17 (dd, J=5.2, 1.8 Hz, 1H), 2.23 (s, 6H), 2.55(dd, J=6.0, 1.6 Hz, 1H), 3.07 (m, 1H), 3.20 (dd, J=14.4, 7.8 Hz, 1H),3.52 (dd, J=14.3, 5.7 Hz, 1H), 4.95 (s, 2H), 7.08 (d, J=9.0 Hz, 2H),7.07 (d, J=9.2 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H);¹³C NMR (126 MHz, CDCl₃) δ 9.7, 24.4, 24.5, 26.3, 54.7, 62.8, 117.0,117.6, 121.5, 122.0, 130.9, 132.0, 133.8, 140.6, 152.4, 163.3; HRMS-ESI(m/z): [M+H]⁺, calcd for C₂H₂₀NO₈S₂, 478.0625. found, 478.0625.

4-Fluoro-2-(methoxymethoxy)-1-nitrobenzene (15)

5-Fluoro-2-nitrophenol (10 g, 63 mmol, 99%) was dissolved in anhydrousDMF (100 mL) in an oven-dried flask. The solution was stirred under anatmosphere of nitrogen and cooled in an ice-water bath. Sodium hydride(3.0 g, 75 mmol) was added with stirring, after which chloro methylether(5.3 g, 66 mmol) was added dropwise. The resulting mixture was aged atroom temperature for 1 h. The reaction was quenched with MeOH, dilutedwith ether and washed with water and brine. The ether layer was driedover anhydrous Na₂SO₄ and concentrated in vacuo. Purification of theproduct by silica gel chromatography (hexanes/EtOAc=1/7) gave the titlecompound in 88% yield. ¹H NMR (500 MHz, CDCl₃) δ 3.53 (s, 3H), 5.30 (d,J=2.0 Hz, 2H), 6.78 (dd, J=7.3, 9.1 Hz, 1H), 7.06 (dt, J=2.3, 10.4 Hz,1H), 7.91 (dd, J=6.0, 9.0 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 57.0,95.6, 105.0 (d, J=26.3 Hz), 108.8 (d, J=23.0 Hz), 127.8 (d, J=10.7 Hz),152.8 (d, J=11.5 Hz), 165.5 (d, J=255.9 Hz). HRMS (FAB) calcd forC₈H₈FNNaO₄ (M+Na⁺) 224.0330. found 224.0328.

S-(4-(3-(Methoxymethoxy)-4-nitrophenoxy)phenyl) dimethylcarbamothioate(17)

To a round bottom flask was added dimethylcarbamothioate 16 (2.1 g, 11mmol), compound 15 (2.5 g, 12 mmol), DMF (50 mL) and Cs₂CO₃ (7.1 g, 22mmol). The resulting mixture was stirred for 24 h, followed byfiltration over silica gel. The solvent was evaporated and the productwas purified by silica gel chromatography (hexanes/EtOAc=2/1) to give 17as a solid in 88% (3.5 g). ¹H NMR (500 MHz, CDCl₃) 3.05 (br. s., 3H),3.12 (br. s., 3H), 3.53 (s, 3H), 5.28 (s, 2H), 6.61 (ddd, J=0.8, 2.5,9.1 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 7.12-7.05 (m, 2H), 7.56-7.50 (m,2H), 7.93-7.88 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 37.1, 37.2, 57.1,95.5, 107.1, 110.4, 120.5, 125.1, 127.9, 135.7, 137.9, 153.0, 156.1,162.0, 166.9. HRMS (FAB) calcd for C₁₇H₁₉N₂O₆S (M+H⁺) 379.0958. found379.0945.

t-Butyl(4-(4-((dimethylcarbamoyl)thio)phenoxy)-2-(methoxymethoxy)phenyl)carbamate(18)

A solution of 17 (2.5 g, 6.6 mmol) in MeOH/H₂O (30 mL/15 mL) was treatedwith iron (1.9 g, 34 mmol) and NH₄Cl (0.35 g, 6.5 mmol) and theresulting mixture was heated at reflux for 2 h. The crude reactionmixture was filtered through Celite and the filtrate was concentrated invacuo. The residue was dissolved in EtOAc and was washed with water. Theorganic layer was separated and the aqueous layer was washed with EtOAc.The combined organic portions were dried over anhydrous Na₂SO₄. Thesolvent was removed under reduced pressure to provide the amine as asolid (1.9 g, 5.5 mmol, 83%). This product was dissolved in MeOH (30mL), was treated with TEA (0.6 g, 5.9 mmol) and Boc₂O (1.9 g, 8.4 mmol,97%) and was stirred at room temperature for 24 h. The solvent wasremoved under reduced pressure and the product was purified by silicagel chromatography (hexanes/EtOAc=3/1) to give the title compound (1.9g, 76%). ¹H NMR (500 MHz, CDCl₃) δ 1.54 (s, 9H), 3.02 (br. s., 3H), 3.08(br. s., 3H), 3.48 (s, 3H), 5.18 (s, 2H), 6.71 (dd, J=2.6, 8.8 Hz, 1H),6.90 (d, J=2.6 Hz, 1H), 6.97-6.92 (m, 2H), 7.00 (br. s., 1H), 7.42-7.36(m, 2H), 8.05 (br. s., 1H). ¹³C NMR (126 MHz, CDCl₃) δ 28.4, 36.9, 56.5,80.5, 95.3, 107.2, 113.6, 117.7, 119.3, 121.6, 125.3, 137.4, 146.5,150.6, 152.9, 159.4, 167.4. HRMS (FAB) calcd for C₂₂H₂₉N₂O₆S (M+H⁺)449.1741. found 449.1735.

t-Butyl(2-(methoxymethoxy)-4-(4-((oxiran-2-ylmethyl)thio)phenoxy)phenyl)-carbamate(19)

To a solution of compound 18 (0.65 g, 1.5 mmol) in anhydrous MeOH (10mL) was added potassium hydroxide (0.42 g, 7.5 mmol). The mixture wasrefluxed for 4 h and then cooled to room temperature. Epichlorohydrin(0.21 g, 2.3 mmol) was added dropwise and the mixture was stirred atroom temperature for 15 min, after which the solvent was removed underreduced pressure. The concentrate was diluted with water and extractedwith EtOAc. The combined organic extracts were dried over anhydrousNa₂SO₄, the suspension was filtered, followed by concentration of thefiltrate in vacuo. Purification by silica gel chromatography(hexanes/EtOAc=4/1) gave 19 in 68% yield (0.43 g) ¹H NMR (500 MHz,CDCl₃) δ 1.53 (s, 9H), 8.03 (br. s., 1H), 2.47 (dd, J=2.6, 5.0 Hz, 1H),2.77 (t, J=4.4 Hz, 1 H), 2.85 (dd, J=6.1, 13.9 Hz, 1H), 3.12-3.05 (m,1H), 3.18-3.12 (m, 1H), 5.18 (s, 2H), 3.48 (s, 3H), 6.66 (dd, J=2.6, 8.8Hz, 1H), 6.92-6.85 (m, 3H), 6.98 (br. s., 1H), 7.44-7.37 (m, 2H). ¹³CNMR (126 MHz, CDCl₃) δ 28.5, 38.2, 47.6, 51.3, 56.5, 80.6, 95.4, 106.8,113.1, 118.4, 119.4, 125.1, 128.0, 131.8, 133.8, 146.6, 151.2, 152.9,157.9. HRMS (FAB) calcd for C₂₂H₂₈NO₄S (M+H⁺) 434.1632. found 434.1637.

t-Butyl(2-(methoxymethoxy)-4-(4-((oxiran-2-ylmethyl)sulfonyl)phenoxy)phenyl)-carbamate(20)

Compound 19 (0.44 g, 1.0 mmol) was dissolved in CH₂Cl₂ (10 ml) andcooled in an ice-water bath. It was treated with m-CPBA (0.48 g, 2.1mmol, 77%) and the resulting white suspension was stirred at roomtemperature for 10 min. The mixture was filtered and the filtrate waswashed with saturated Na₂S₂O₃, followed by saturated NaHCO₃. The organiclayer was separated and the aqueous layer was washed with CH₂Cl₂. Thecombined organic solution was dried over anhydrous Na₂SO₄, thesuspension was filtered and the filtrate was concentrated in vacuo.Purification of the product by silica gel chromatography(hexanes/EtOAc=2/1) gave the title compound in 89% yield (0.42 g). ¹HNMR (500 MHz, CDCl₃) δ 1.54 (s, 9H), 2.48 (dd, J=2.2, 4.8 Hz, 1H), 2.82(t, J=4.5 Hz, 1H), 3.28-3.19 (m, 1H), 3.38-3.28 (m, 2H), 3.49 (s, 3H),5.20 (s, 2H), 6.73 (dd, J=2.6, 8.8 Hz, 1H), 6.91 (d, J=2.6 Hz, 1H), 7.03(s, 1H), 7.09-7.04 (m, 2H), 7.89-7.83 (m, 2H), 8.13 (br. s., 1H). ¹³CNMR (126 MHz, CDCl₃) δ 28.5, 46.0, 46.1, 56.6, 59.8, 80.9, 95.4, 107.5,114.2, 117.2, 119.5, 126.3, 130.6, 132.3, 146.7, 149.4, 152.9, 163.5.HRMS (FAB) calcd for C₂₂H₂₈NO₈S (M+H⁺) 466.1530. found 466.1543.

t-Butyl(2-(methoxymethoxy)-4-(4-((thiiran-2-ylmethyl)sulfonyl)phenoxy)phenyl)-carbamate(21)

To a solution of 20 (0.40 g, 0.86 mmol) in CH₂Cl₂ (5 mL) was added amixture of thiourea (0.10 g, 1.3 mmol, 99%) in methanol (5 mL). Theresulting mixture was stirred for 24 h at room temperature, after whichthe solvent was removed under reduced pressure. The residue waspartitioned between CH₂Cl₂ and water. The organic layer was dried overanhydrous Na₂SO₄ and was filtered. Evaporation of solvent andpurification by silica gel chromatography (hexanes/EtOAc=4/1) gave 0.34g of 21 (83%). ¹H NMR (500 MHz, CDCl₃) δ 1.53 (s, 9H), 2.14 (dd, J=1.8,5.0 Hz, 1H), 2.52 (dd, J=1.5, 5.9 Hz, 1H), 3.04 (dq, J=5.6, 7.8 Hz, 1H),3.15 (dd, J=8.0, 14.2 Hz, 1H), 3.47 (s, 3H), 3.51 (dd, J=5.6, 14.4 Hz,1H), 5.19 (s, 2H), 6.72 (dd, J=2.6, 8.8 Hz, 1H), 6.91 (d, J=2.6 Hz, 1H),7.08-7.01 (m, 3H), 7.85-7.80 (m, 2H), 8.16-8.08 (m, 1H). ¹³C NMR (126MHz, CDCl₃) δ 24.4, 26.2, 28.5, 56.6, 62.7, 80.8, 95.3, 107.3, 114.1,117.3, 119.4, 126.2, 130.8, 131.6, 146.6, 149.3, 152.8, 163.5. HRMS(FAB) calcd for C₂₂H₂₈NO₇S₂ (M+H⁺) 482.1302. found 482.1301.

2-Amino-5-(4-((thiiran-2-ylmethyl)sulfonyl)phenoxy)phenol (22)

To a solution of compound 21 (0.10 mg, 0.21 mmol) in methanol (5 mL) wasadded a few drops of conc. HCl. After the mixture was stirred at refluxfor 1 h, the solvent was evaporated in vacuo. The crude product wastaken up into water and EtOAc. Layers were separated and the aqueouslayer was washed with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄, the suspension was filtered and the filtrate wasconcentrated in vacuo. Purification by silica gel chromatography(hexanes/EtOAc=1/1) gave 22 in 95% yield (66 mg). ¹H NMR (500 MHz,CDCl₃) δ2.14 (dd, J=1.3, 4.9 Hz, 1H), 2.18 (d, J=1.0 Hz, 1H), 2.56-2.49(m, 1H), 3.08-3.00 (m, 1H), 3.17 (dd, J=7.8, 14.4 Hz, 1H), 3.51 (dd,J=5.6, 14.2 Hz, 2H), 6.54-6.46 (m, 2H), 6.80-6.73 (m, 1H), 7.07-6.97 (m,2H), 7.80 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ24.4, 26.3, 62.8, 108.5,113.1, 117.2, 117.9, 130.7, 131.1, 131.9, 145.9, 147.3, 164.1. HRMS(FAB) calcd for C₁₅H₁₆NO₄S₂ (M+H⁺) 338.0515. found 338.0507.

Example 2 Experimental Inhibition Data

Fluorescence Enzymatic Activity Assays.

The enzymatic activity of MMP-2, MMP-9, and MMP-7 was monitored with thefluorescence quenched substrate MOCAcPLGLA₂pr(Dnp)-AR-NH₂. Fluorescencewas measured with a Photon Technology International (PTI)spectrofluorometer interfaced to a Pentium computer, equipped with theRatioMaster™ and FeliX™ hardware and software, respectively. The cuvettecompartment was thermostated at 25° C. Substrate hydrolysis wasmonitored at emission and excitation wavelengths of 328 and 393 nm andexcitation and emission band passes of 1 and 3 nm, respectively.Fluorescence measurements were taken every 4 seconds. Less than 10%hydrolysis of the fluorogenic substrate was monitored, as described byKnight. Knight, C. G. Methods Enzymol. 1995, 248, 18-34. Stromelysin 1enzymatic activity was monitored using the synthetic fluorogenicsubstrate MOCAcRPKPVE-Nva-WRK(Dnp)-NH₂ (Peptides International,Louisville, Ky.) at excitation and emission wavelengths of 325 and 393nm and excitation and emission band passes of 1 and 3 nm, respectively.

The following buffers were used in experiments with enzymes: Buffer C(50 mM HEPES at pH 7.5, 150 mM NaCl, 5 mM CaCl₂, 0.02% Brij-35); bufferR (50 mM HEPES at pH 7.5, 150 mM NaCl, 5 mM CaCl₂, 0.01% Brij-35, and 1%v/v Me₂SO) and buffer D (50 mM Tris at pH 7.5, 150 mM NaCl, 5 mM CaCl₂,and 0.02% Brij-35).

Enzymes and Protein Inhibitors.

Human pro-MMP-2, pro-MMP-9, TIMP-1 and TIMP-2 were expressed in HeLa S3cells infected with the appropriate recombinant vaccinia viruses andwere purified to homogeneity, as previously described. See Fridman etal., J. Biol. Chem. 1992, 267, 15398-15405 and Fridman et al., Biochem.J. 1993, 289, 411-416. Pro-MMP-2, pro-MMP-9, TIMP-1 and TIMP-2concentrations were determined using the extinction coefficients of122,800, 114,360, 26,500 and 39,600 M⁻¹ cm⁻¹, respectively. To obtainactive MMP-2, pro-MMP-2 (7.3 μM) was incubated at 37° C. for 1 h with 1mM p-aminophenyl-mercuric acetate (APMA) (dissolved in 200 mM Tris) inbuffer C. The enzyme solution was dialyzed against buffer D at 4° C. toremove APMA. Active MMP-9 was obtained by incubating pro-MMP-9 (1 μM)with heat-activated recombinant human stromelysin 1 (68 nM) (MMP-3,generously provided by Dr. Paul Cannon, Center for Bone and JointResearch, Palo Alto, Calif.) at 37° C., for 2.5 h in buffer C.

The resulting solution was subjected to gelatin-agarose chromatographyto remove stromelysin 1. MMP-9 was eluted with buffer D containing 10%DMSO and dialyzed against the same buffer without DMSO to remove theorganic solvent. Pro-MMP-2 and pro-MMP-9 activation reactions weremonitored using the fluorescence quenched substrateMOCAcPLGLA2pr(Dnp)-AR-NH₂ (Peptides International, Louisville, Ky.;PLGLAAAR), as will be described below. The MMP-2 and MMP-9concentrations were determined by titration with TIMP-1.

Kinetic Analyses.

Progress curves were obtained by adding enzyme (0.5-2 nM) to a mixtureof fluorogenic substrate (5-7 μM) and varying concentrations ofinhibitor in buffer R containing 5-15%

DMSO (final volume 2 ml), in acrylic cuvettes with stirring andmonitoring the increase in fluorescence with time for 15-30 minutes. Theprogress curves were nonlinear least squares fitted to Equation 1(Muller-Steffner et al., J. Biol. Chem. 1992, 267, 9606-9611.):

F=v _(s) t+I(v _(o) −v _(s))(1−exp(−kt))/k+F ₀  (1)

where v_(o) represents the initial rate, v_(s), the steady state rate,k, the apparent first order rate constant characterizing the formationof the steady-state enzyme-inhibitor complex and F_(o), the initialfluorescence, using the program SCIENTIST (MicroMath ScientificSoftware, Salt Lake City, Utah). The obtained k values, v_(o) and v_(s)were further analyzed according to Equations 2 and 3 for a one-stepassociation mechanism:

k=k _(off) +k _(on) [I]/(1+[S]/K _(m))  (2)

(v _(o) −v _(s))/v _(s) =[I]/(K _(i)(1+[S]/K _(m)))  (3)

Intercept and slope values, obtained by linear regression of the kversus inhibitor concentration plot (Equation 2), yielded theassociation and dissociation rate constants k_(on) and k_(off),respectively, and the inhibition constant K_(i) (k_(off)/k_(on)).Alternatively, K_(i) was determined from the slope of the(v_(o)−v_(s))/v_(s) vs [I] plot according to Equation 3.

The dissociation rate constants were determined independently from theenzyme activity recovered after dilution of a pre-formedenzyme-inhibitor complex. To this end, typically 200 nM of enzyme wasincubated with 1 μM of inhibitor for a sufficient time to reachequilibrium (>45 min) at 25.0° C. The complex was diluted into 2 mL ofbuffer R containing fluorogenic substrate (5-7 μM final concentration)to a final enzyme concentration of 1 nM. Recovery of enzyme activity wasmonitored for ˜30 min. The fluorescence versus time trace was fitted,using the program SCIENTIST, to Equation 4:

F=v _(s) t+(v _(o) −v _(s))(1−exp(−k _(off)))/k _(off) +F ₀  (4)

where v_(o) represents the initial rate (very small), v_(s), the rateobserved when the E.I complex is completely dissociated and k_(off), thefirst order rate constant when the E.I dissociation.

Analysis for linear competitive inhibition was performed in thefollowing manner. Initial rates were obtained by adding enzyme (0.5-2nM) to a mixture of fluorogenic substrate (5-7 μM) and varyingconcentrations of inhibitor in buffer R, containing 5-15% DMSO (finalvolume 1 mL) in semi-micro quartz cuvettes, and monitoring the increasein fluorescence with time for 5-10 minutes. The fluorescence versus timetraces were fitted by linear regression analysis using FeliX™. Theinitial rates were fitted to Equation 5 (Segel, I. H. in: EnzymeKinetics, Wiley Inc., New York, 1975, pp. 104):

v/V _(max) =S/(K _(m)(1+I/K _(i))+S)  (5)

where v and V_(max) represent the initial and maximal velocities, S andI, the substrate and inhibitor concentrations, respectively, K_(m) theMichaelis-Menten constant for the substrate-enzyme reaction and K_(i)the inhibition constant, using the program SCIENTIST.

TABLE 2 Inhibition Data of Certain Specific Compounds. Half-lifeHalf-life Water in human plasma in human blood Cmpd. MMP-2 MMP-9Solubility at 37° C. (min) at 37° C. (min) 11a ¹k_(on): 1.9 ± 0.6k_(on): 0.21 ± 0.04 >10 mg/mL 32.4 ± 2.7 27.1 ± 2.5 ²k_(off): 8.2 ± 0.9k_(off): 6.5 ± 0.6 ³K_(i): 0.44 ± 0.05 K_(i): 3.1 ± 0.3 11b k_(on): 3.4± 0.1 k_(on): 0.27 ± 0.04 >10 mg/mL 25.1 ± 5.2 15.3 ± 1.9 k_(off): 2.1 ±0.9 k_(off): 4.2 ± 0.7 K_(i): 0.062 ± 0.025 K_(i): 1.6 ± 0.3 11c k_(on):2.5 ± 0.1 k_(on): 2.3 ± 0.1 >10 mg/mL 32.8 ± 3.6 27.9 ± 3.8 k_(off): 1.8± 1.6 k_(off): 12.0 ± 0.7 K_(i): 0.069 ± 0.064 K_(i): 5.4 ± 0.3 11dk_(on): 7.6 ± 2.9 k_(on): 0.031 ± 0.006 >10 mg/mL 29.5 ± 0.7 25.4 ± 0.1k_(off): 1.5 ± 0.1 k_(off): 6.0 ± 0.3 K_(i): 0.52 ± 0.20 K_(i): 19.6 ±1.0 11e k_(on): 1.5 ± 0.1 k_(on): 0.044 ± 0.004 >10 mg/mL 11.8 ± 0.5 5.9 ± 0.6 k_(off): 6.1 ± 2.1 k_(off): 8.3 ± 2.3 K_(i): 0.42 ± 0.15K_(i): 18.7 ± 5.6 14 K_(i): 2.4 ± 0.6 37% inhibition *1.01 (±0.02)  1.6± 0.4 at 80 μM μg/mL ¹k_(on): ×10³ M⁻¹ s⁻¹ ²k_(off): ×10⁻⁴ s⁻¹ ³K_(i):in μM *in 100% water; solubility calculated using ε of MIK-G6(p-N-acetyl SB-3CT)

TABLE 3 Kinetic Parameters for Inhibition of MMPs by Compounds 11d, 6,and 22. k_(on): k_(off): Compound MMP ×10³ M⁻¹ s⁻¹ ×10⁻⁴ s⁻¹ K_(i): inμM 11d MMP-2  7.6 ± 2.9 1.5 ± 0.1 0.52 ± 0.20 MMP-9  0.031 ± 0.006 6.0 ±0.3 19.6 ± 1.0  MMP-1  — — 43% inhibition at 1 mM MMP-3  — — 40.5 ± 1.2 MMP-7  — — 160 ± 14  MMP-14 0.42 ± 0.01 12.0 ± 0.1  28.9 ± 2.3  6 MMP-2 8.9 ± 0.2 2.1 ± 1.3 0.024 ± 0.015 MMP-9  0.61 ± 0.01 5.3 ± 0.7 0.87 ±0.11 MMP-1  — — No inhibition at 20 μM MMP-3  — — 3% inhibition at 20 μMMMP-7  — — No inhibition at 200 μM MMP-14 8.0 ± 0.4 8.0 ± 0.3  0.1 ±0.006 22 MMP-2  1.7 ± 0.1 1.4 ± 0.7 0.078 ± 0.043 MMP-9  1.07 ± 0.12 5.3± 1.0 0.49 ± 0.11 MMP-1  — — 11% inhibition at 300 μM MMP-3  — — 54%inhibition at 300 μM MMP-7  — — 116 ± 13  MMP-14 2.69 ± 0.27 7.02 ± 1.610.26 ± 0.07

TABLE 4 Half-lives in Liver Microsomes. Half-life in min Compound MouseRat Human 11d >60 59.3 ± 4.5 >60 6 27.3 ± 2.1 23.4 ± 0.7 >60

As can be observed from the data above, the compounds described hereinhave significantly improved solubilities over SB-3CT and convert to theactive compound 6 in human blood and plasma within 30 minutes. Themethods used to obtain the data of Table 2 are known in the art and aredescribed, for example, by Brown et al., J. Amer. Chem. Soc. 2000,122(28), 6799-6800, and the references cited therein. Additional usefulassays and techniques are described in U.S. Patent Publication No.2009/0209615 (Lipton et al.), which is incorporated herein by referencein its entirety. Compound 11d was evaluated for its mutagenic potentialby measuring its ability to induce reverse mutations at selected loci ofAmes II mixed strains and strain TA98 in the presence and absence of ratliver S9 metabolic activation at six concentrations up to 1 mg/mL(equivalent to 300 μM). Compound 11d was negative (non-mutagenic) inthis Ames mutagenicity assay with and without metabolic activation.

Example 3 Pharmaceutical Dosage Forms

The following formulations illustrate representative pharmaceuticaldosage forms that may be used for the therapeutic or prophylacticadministration of a compound of a formula described herein, a compoundspecifically disclosed herein, or a pharmaceutically acceptable salt orsolvate thereof (hereinafter referred to as ‘Compound X’):

(i) Tablet 1 mg/tablet ′Compound X′ 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0 (ii) Tablet 2 mg/tablet ′Compound X′ 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule ′Compound X′10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/mL) mg/mL′Compound X′ (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxidesolution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1mL (v) Injection 2 (10 mg/mL) mg/mL ′Compound X′ (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 0.1N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosol mg/can ′CompoundX′ 20 Oleic acid 10 Trichloromonofluoromethane 5,000Dichlorodifluoromethane 10,000 Dichlorotetrafluoroethane 5,000

These formulations may be prepared by conventional procedures well knownin the pharmaceutical art. It will be appreciated that the abovepharmaceutical compositions may be varied according to well-knownpharmaceutical techniques to accommodate differing amounts and types ofactive ingredient ‘Compound X’. Aerosol formulation (vi) may be used inconjunction with a standard, metered dose aerosol dispenser.Additionally, the specific ingredients and proportions are forillustrative purposes. Ingredients may be exchanged for suitableequivalents and proportions may be varied, according to the desiredproperties of the dosage form of interest.

While specific embodiments have been described above with reference tothe disclosed embodiments and examples, such embodiments are onlyillustrative and do not limit the scope of the invention. Changes andmodifications can be made in accordance with ordinary skill in the artwithout departing from the invention in its broader aspects as definedin the following claims.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A method of treating a disease or condition thatis modulated by a matrix metalloproteinase (MMP) comprisingadministering to a patient in need of such treatment an effective amountof a compound of Formula A:

wherein X is O, NH or —S—NH—, and R¹ is:

wherein L is O, NH, —OCH₂O—, or —C(═O)O—CH₂O—; each Y is independently—NH₂, —CO₂H, —P(═O)(OH)₂, —OP(═O)(OH)₂, Het, or a guanidine moiety; Hetis a 5 or 6 membered heterocyclic ring comprising 1, 2, or 3 heteroatomsselected from O, N, S, or P, wherein the ring optionally includes one ortwo sites of unsaturation and the ring is optionally substituted with 1,2, or 3 oxo, halo, nitro, or methyl groups; and R³ is an amino acid or alinear or branched chain of two to five amino acids, linked to X or thecarbonyl of R¹ by a nitrogen or sulfur atom; or a salt thereof; whereinthe compound has an aqueous solubility of at least 5 mg/mL; therebytreating the disease or condition.